Stem Cell Treatments for Cancer Essay.


Ehab Albalawi, a 40-year-old male, was admitted to Beijing Puhua International Hospital due to progressive weakness and numbness of three year’s duration involving his left arm and leg. He was diagnosed with multiple sclerosis.Stem Cell Treatments for Cancer Essay.


Medical Condition before Stem Cell Treatment for Multiple Sclerosis
In 2010, Ehab started to loose strength and suffer from numbness on the left side of his body. Until 2013, he felt that the left half of his body was partially paralyzed. According to his admission exam, his deep tendon reflexes were normal on his right side but hyper-tonic on the left. MRI results were consistent with his clinical and lab diagnosis of MS.Stem Cell Treatments for Cancer Essay.

Stem Cell Treatment & TCM for Multiple Sclerosis
After admission, several medical protocols were applied, including: improvement of cerebral blood circulation and nutrition, stem cell treatment (lumbar puncture + IV), combined with Traditional Chinese Medicine and rehabilitation training.Stem Cell Treatments for Cancer Essay.

Originally, the treatment plan for Multiple Sclerosis was for 3 weeks, but since the treatment worked so well his treatment plan was extended to 2 months with additional rounds of stem cell therapy. After finishing 5 rounds of stem cell treatment, he stayed in the hospital for Traditional Chinese Medicine and rehabilitation physiotherapy, to help each consolidate the gains made by his stem cell treatment.Stem Cell Treatments for Cancer Essay.

Medical Condition after Stem Cell Treatment for Multiple Sclerosis
After 2 months treatment, Ehab began to be able to move his left arm and leg much better, and began to be able to walk faster and with greater stability. In a word, he began to feel much more normal. His muscle strength improved, with greater strength and flexibility. Further, spontaneous pains in his left arm began to resolve. Some mild residual numbness remained in left hand, but is diminishing with the passage of time.Stem Cell Treatments for Cancer Essay.

Before the treatment for Multiple Sclerosis, Ehab was unable to lift his left leg to a cross-legged sitting position, but he has been very much able to do so after treatment. The most amazing thing has been to watch him doing the “single leg squat” with his left leg only. This test requires a lot of muscle strength and balance, and is considered difficult by any standard.Stem Cell Treatments for Cancer Essay.

It has been gratifying for patient and staff to witness the improvements in strength, tone and sensation for patient Ehab, especially regarding his previously afflicted left side.

Autologous (Self-Donated)

Autologous Transplantation – In this type of bone marrow transplant, the patient is given high dose of chemotherapy after which the collected peripheral blood stem cells are infused. The chemotherapy is done to kill the cancer cells (disease) in the body. The infusion of the peripheral blood stem cells replaces the marrow that was destroyed by the chemotherapy.Stem Cell Treatments for Cancer Essay.

Allogeneic (Donor) Transplants Using Matched Sibling

Allogeneic Transplantation – In allogeneic transplant, the patient is given high-dose of either chemotherapy and/or radiation therapy which is then followed by the infusion of the donor’s bone marrow, cord blood or the peripheral blood stem cells. The peripheral blood stem cells, marrow, or cord blood cells are taken from an appropriate HLA (immune) which could be matched.Stem Cell Treatments for Cancer Essay.

Allogeneic Transplants Using Unrelated Donors

Allogeneic Transplantation – In allogeneic transplant, the patient is given high-dose of either chemotherapy and/or radiation therapy which is then followed by the infusion of the donor’s bone marrow, cord blood or the peripheral blood stem cells. The peripheral blood stem cells, marrow, or cord blood cells are taken from an appropriate HLA (immune) which could be an unrelated donor.Stem Cell Treatments for Cancer Essay.

Allogeneic Transplants Using Haploidentical (Half-Matched) Donors

Haploidentical Donor Transplantation – In Haploidentical Donor transplantation, the procedure involves HLA half-matched (haplotype) donor, the donors could be biological parents, children, or half matched siblings for the allogeneic transplantation. The capability to utilize Haploidentical donors is of unique significance to patients who in the past had very limited sibling and unrelated donor options.Stem Cell Treatments for Cancer Essay.

Allogeneic Transplants Using Umbilical Cord Blood

Allogeneic Transplantation – a further new alternative for those with no matched donor is blood from the umbilical cord of a baby. The cells are still “naïve”, the immune cells in the cord blood, which means they have not until now become functional in attacking the other cells. This immaturity makes them less likely to attack the transplant recipient’s tissues—therefore, cord blood stem cells do not need to be such a close match.Stem Cell Treatments for Cancer Essay.

Reduced-Intensity Conditioning Allogeneic Transplants

Reduced Intensity Transplantation – In this type of allogeneic transplants, utilizes lesser doses of chemotherapy or radiation therapy. This alternative is for the people who may not be capable of bearing a full-intensity or myeloablative allogeneic transplant (for the older ones or who might have other medical problems). The reduced intensity transplants are performed on an inpatient or outpatient, which depends on the treatment package.Stem Cell Treatments for Cancer Essay.

Purpose: To evaluate the publics’ level of awareness regarding the role of stem cell transplantation in treating cancers. Method: questionnaires were distributed to the public and then the data was collected and analyzed. Results: the data from a 100 participants showed that the majority of public were aware of the general concept of stem cell transplantation, however, they had no knowledge of its role in treating cancer. Conclusion: there is an increased need to educate, and raise the publics’ awareness of the role, uses, and contribution of stem cell transplants in treating cancers.Stem Cell Treatments for Cancer Essay.

1. Introduction:
– Stem Cell Transplant:
All blood cells in the body start as immature, young, cells “Hematopoietic stem cells, meaning blood-forming cells. Most stem cells live in the bone marrow, and then they divide to form new blood cells and stay in the bone marrow until they are mature. Once they are mature, they leave the bone marrow into the blood stream (Craddock, 2009).Stem Cell Treatments for Cancer Essay.
Stem cell transplant is used to restore stem cells and blood production when bone marrow is destroyed by a disease, chemotherapy, or radiation therapy. The sources of hematopoietic stem cell transplants vary and can be taken from 3 different sources in the body: The bone marrow of large bones, e.g. Pelvis; Peripheral Blood, Most commonly used; and from Umbilical Cord Blood. All of which are categorized under the Hematopoietic Stem Cell Transplant (Heredia, 2014).
Hematopoietic stem cell transplants are also used prior to initiating cancer therapy for some patients, as the cells are able to transform into any cell type, and further ensure that patients’ bodies are capable of producing enough cells (Craddock, 2009).Stem Cell Treatments for Cancer Essay.

– History of Stem Cell transplants:
The Idea: The first bone marrow transplant was delivered orally to patients. They had to eat healthy bone marrow in hopes to find its way into the cell producing cavities. Doctors had the right idea, but the method of treatment was not particularly successful (Pablo, 2015). Eventually, laboratory experiments on mice demonstrated that injured mice with damaged bone marrow were able to become healthy after they were injected with healthy bone marrow from healthy mice. Physicians then started speculating whether such procedure would work on humans successfully (Pablo, 2015).
In 1956, Dr. E. Donnall Thomas performed the first human bone marrow transplant between two identical twins in New York. Thomas stated that bone marrow infusion from identical twins after total body irradiation could result in complete leukemia remission (Liras, 2010).Stem Cell Treatments for Cancer Essay.
Jean Dansset, a French medical researcher, then made a breakthrough regarding the human immune system in 1958. He described it as “Human Histocompatibility Antigens”, which are proteins of the most cell surfaces. The immune system uses these proteins to decide which cells belong to the body and which do not. The better the antigen match between the donor and the recipient, the more fitting the bone marrow would be, shifting the main focus of preparing such transplants to the HLA-Antigen match in order to result in a successful transplant (Liras, 2010)).Stem Cell Treatments for Cancer Essay.
Dr. Robert A. Good has done the first successful bone marrow transplant between siblings in 1968. The transplant was performed on a 4-month-old baby who had inherited severe combined immunodeficiency syndrome, or Bubble boy syndrome. The donor was the patients’ 8-year-old sister who had a good HLA-matching (Pablo, 2015).Stem Cell Treatments for Cancer Essay.
In 1973, a medical team at Memorial-Sloan Kettering Cancer Center in New York carried out the first successful unrelated bone marrow transplant. The transplant was performed on a 5-year-old patient suffering from Combined Immunodeficiency syndrome. The matching donor was found in Denmark through the Blood Bank at Rigshospitulet In Copenhagen. Multiple infusions of bone marrow was delivered to the patient, and after the seventh infusion, engraftment and hematologic normal functions were achieved (Figuerres, 2000).Stem Cell Treatments for Cancer Essay.
In 1986, the American Congress approved the formation of the proposed “National Bone Marrow Donor Registry (NBMDR)”, registering 39 donors by the end of that year. From that point in time, medical and cancer centers worldwide started performing bone marrow transplants (Pablo, 2015).
By 1999, scientists have identified new sources of blood-forming cells that can be used in transplantation; these were the introduction of peripheral blood, and umbilical cord blood stem cell transplantations. The discovery of the other sources led to the treatment of many life-threatening diseases that were impossible to cure in the medical therapy field (Pablo, 2015).Stem Cell Treatments for Cancer Essay.
2. Objective:
To evaluate the publics’ perception about the applications of hematopoietic stem cell therapy.

3. Literature Review:
3.1. Obtaining Stem Cells:
Stem cells can be obtained from different body tissues or organs, and whether the stem cells collected come from the patients own body or a donor (Gorin, 2000).
An Autologous Transplants:
In this case, stem cells come from the own body of the patient before being infected with a disease. They can also be collected once a patient is fully treated from a disease, if suspecting recurrence of a disease. Autologous stem cell transplants are also called “Stem Cell Support” as the stem cells taken are from the own body of the patient and not literally transplanted from a donor (Figuerres, 2000).Stem Cell Treatments for Cancer Essay.
An Allogeneic Transplants:
Allogeneic transplants involve collecting stem cells from a donor, usually a sibling or a close relative, with good HLA-matching. In some cases, allogeneic stem cells transplants can succeed between unrelated donor and patient, as long as there is a good HLA-matching (Hough, 2009).Stem Cell Treatments for Cancer Essay.
Allogeneic stem cells come from three different sources of the body: Bone Marrow; The Blood Stream (Peripheral blood); and Umbilical Cord Blood (from new born), says Pidala, 2009.
1-) Bone Marrow Stem Cells:
Bone marrow is the spongy tissue in the center of large bones; its function is to make blood cells that circulate in the body system. They also form into immune cells that fight foreign cells that are recognized by the body as invaders or infections. Bone marrow is very rich of stem cells especially in the pelvic region, which contains most marrow with large stem cell numbers. It is the most common, but not most convenient, source of stem cell transplantation (Hough, 2009).Stem Cell Treatments for Cancer Essay.
The Donor of such stem cells must be put into general anesthesia as a large needle is put into the hip until it reached the marrow of the pelvic bone. Then the thick liquid marrow is pulled in the syringe, this process is repeated until enough marrow is collected. The arrow is then filtered and frozen until it is needed for use (Hough, 2009).
When a patient is set for the transplant, the marrow is melted and softened and given into the vein, just like in the process of blood transfusion. The stem cells then find their way to the recipients’ bone marrow and begin to divide over time. The new blood cells formed can be assessed by blood tests in about 2-4 weeks of the transplant (Figuerres, 2000).Stem Cell Treatments for Cancer Essay.
2-) Peripheral Blood Stem Cells:
When collecting stem cells from the blood, the donor is given hormone-like substance called “growth factors” before harvesting stem cells from their blood system. Growth factors cause stem cells to travel from bone marrow into the blood stream and cause them also to grow faster (Akkök, 2011).Stem Cell Treatments for Cancer Essay.
When harvesting, a catheter is connected to the donors’ large vein and is connected to a tube that carries blood into a special machine. The machine separates stem cells from other blood components and the rest of the components are guided back to the donor’s body after stem cells are collected. This process lasts for 4-6 hours and may be repeated for a few days until enough stem cells are collected (Akkök, 2011).Stem Cell Treatments for Cancer Essay.
After the patient has undergone chemotherapy or radiotherapy, stem cells are infused into a vein, in the same way illustrated above in the bone marrow stem cell transplant, and the new cells can be measured a few days sooner than that of bone marrow transplant, usually within 10-20 days (Figuerres, 2000).Stem Cell Treatments for Cancer Essay.

3-) Umbilical Cord Blood Stem Cells:
It is the suitable source for patients who cannot find a matched donor among their family members or donors from blood banks, due to its high differential capability and ability to adjust themselves into any immune system. Umbilical cord blood transplants account for about One Third of hematopoietic stem cells transplants. New born babies possess large numbers of stem cells as the blood left in the placenta and umbilical cord can be stored for future use in stem cell transplants. It is usually collected from the blood that is thrown out after a baby is born. The first umbilical cord blood stem cell transplant was done in 1988 and has been increasing ever since. Although only a small number of stem cells can be found using such a procedure, umbilical cord blood stem cells are able to make more cells than that from adult bone marrow (Harris, 2013).Stem Cell Treatments for Cancer Essay.
4-) Oogonial Stem Cells (OSC):
Oogonial stem cells are collected from the ovaries of reproductive-age females, which have the potential of giving birth to new fertility treatment and longing the reproductive life (Powell, 2012).
A team of scientists began by developing a method of labeling and collecting mice ovarian stem cells. They used Fluorescent-activated Cell Sorting (FACS) as a technique to attach antibodies to a protein, Ddx4, which resides on the outer surface of stem cells (Johnson, 2004). This method of labeling has the ability to not include dead or damaged stem cells (White, 2012).Stem Cell Treatments for Cancer Essay.
The team then labeled the cells with green-glowing fluorescent protein to trace the cells and injected the stem cells into fragments of adult human ovarian tissue that was transplanted under the skin of mice. Within one to two weeks after injecting the cells, the team was able to point additional green-glowing cells that were identified as oocytes and that also expressed two of the genetic hallmarks of this cell type (Zou, 2009) and (White, 2009).Stem Cell Treatments for Cancer Essay.
This breakthrough would allow scientists to examine hormones or drugs that might revive these cells to produce eggs in the body, which in turn would lead to slowing women’s biological clock and longing the life or their reproductive system (Powell, 2012).
3.2. The Most Suitable Source of Stem Cells:
As the goal is to transplant healthy stem cells to the patients, the 3 different sources and mechanisms of acquiring stem cells do not have much difference between them. When stem cell transplantation was initially used, all originated from bone marrow. However, the most commonly used currently is peripheral blood stem cell transplantation. Harvesting more stem cells of peripheral blood is a controllable process in which doctors can manage. It is also easier for the doctors to acquire peripheral blood stem cells than bone marrow stem cells even though the process might be more time consuming. The recipients’ blood count, nonetheless, can be measure within shorter periods of time than that of bone marrow stem cell transplants (Gorin, 2000).Stem Cell Treatments for Cancer Essay.
The only disadvantage is that the risk of developing chronic graft-versus-host disease is higher in peripheral blood stem cell transplant that in bone marrow stem cell transplants (Pidala, 2009).
When a good match is hard to find for bone marrow or peripheral blood cell transplants, umbilical cord blood transplants is believed to be the suitable option. Although it is best if cord blood is well matched, it does not need to be closely matched as in the extent of bone marrow and peripheral blood cases as suggested by studies (Pidala, 2009). As for patients with rare tissue type, cord blood is considered an advantage. Moreover, blood cord transplants reduce the severity of chronic graft-versus-host disease, but they take longer to engraft causing high-risk of infections to the patient (Gorin, 2000).Stem Cell Treatments for Cancer Essay.

3.3. Therapy of Leukimia and Lymphomas:
According to Grosicki 2015, Leukemia is cancer that occurs in cells that are usually developed into different types of blood cell. However, the type of leukemia differs and can be categorized into 4 different types as follows:Stem Cell Treatments for Cancer Essay.
-Mature Vs. Immature White Blood Cells:
1-) Acute Leukemia: In acute leukemia, the cancer cells are in the immature phase of blood cells (blasts). This type of leukemia is growing fast as would normal blast cells do. The significance, in this context, is that leukemia cells would not stop dividing and grow faster than normal blast cells, but continue their division and fast multiplication without stopping. Most patients with acute leukemia would live for a few months if no treatment were started. Different types of acute leukemia respond differently to treatment, some would be treated and others are less likely to be cured (Lekakis, 2009).Stem Cell Treatments for Cancer Essay.
2-) Chronic Leukemia: They are cancer cells that affect that mature cells of blood components, but they do not act normally. For example, they are unable to fight viruses, infections and other body invaders, as normal white blood cells would do. In fact, they do not fight such invaders at all. Instead, they survive longer than normal blood cells do; they divide and build in the blood stream, and swarm out normal cells. It is true that chronic leukemia progresses over longer periods of time than in acute leukemia, and patients can adapt to living with tem for many years, they are much tougher than acute leukemia to cure (Grosicki, 2015).
-Type of Bone Marrow Cells Affected:
1-) Myeloid Leukemia: they start in myeloid cells that are immature. For example, in white blood cells, platelet-making cells, or red blood cells.Stem Cell Treatments for Cancer Essay.
2-) Lymphocytic Leukemia: They affect the immature form of lymphocytes. They differ from lymphomas in that lymphocytic leukemia develops from cells of bone marrow, whereas lymphomas develop in cells of the lymph nodes (Grosicki, 2015).

3.3.2. Lymphomas:
Lymphoma is a type of cancer that affects the lymphocyte making them to behave in an abnormal manner. Such abnormality includes that vast division of cells and the longer proliferation of cells. Lymphomas can develop in many parts of the body including lymph nodes, blood, spleen, or other organs (Angelopoulou, 2014).
There are 2 types of lymphoma; these are Hodgkin lymphomas and non-Hodgkin lymphomas.Stem Cell Treatments for Cancer Essay.
1-) Hodgkin Lymphoma (HL):
These are types of lymphomas that involve the Reed-Sternberg Cells in its developmental process. It is neoplastic proliferation of lymphoid cells, the malignancies in this type is in the Reed-Sternberg cells. In most cases, the Reed-Sternberg cells are B-cells and Clonal. They are very large with abundant pale cytoplasm and 2 or more oval lobulated nuclei containing large nucleoli (Ritchie, 2008).
Thomas Hodgkin first assessed HL in 1832, and then Carl Sternberg and Dorothy Reed described the characteristics of Reed-Sternberg cells in 1898 (Adelstein, 2014).Stem Cell Treatments for Cancer Essay.
2-) Non-Hodgkin Lymphoma:
They are cancers of the immune system and can occur almost anywhere in the body, but mostly 80% develops in lymph nodes. Its pathology is dependent on 3 aspects; the cell lineage, the degree of cell differentiation, and the location of the cell of origin. This type of lymphoma can simple start any and travel everywhere (Ritchie, 2008).Stem Cell Treatments for Cancer Essay.

3.4. Pros and Cons of Stem Cell Transplantation:
The controversy of stem cell therapy is mainly dependent on whether its advantages outweigh the disadvantages, its plasticity and degree of differentiation, availability are also of great deal to carrying out stem cell transplantations.
One of the advantages of adult stem cells is that they can be found in a number of tissues and organs in the body, and can be acquired using a variety of techniques depending of which type of stem cells are needed to be collected. Their high differentiation potential to regenerate the tissue or organ that they will reside in and cure is beyond the required threshold for the success of the procedure. For bone marrow stem cell transplantation, the long-term experience of performing the procedure and the familiarity with the method of acquiring, collecting and administering the stem cells makes the success of such procedure foreseeable as it is being performed for more than 3 decades up until now (Habib, 2006).Stem Cell Treatments for Cancer Essay.
In addition, adult stem cells have the ease of identifying homogeneous stem cells and the ease tissue type availability. It is widely availably in such a way that it does not need tissue culture because the number of required stem cells is sufficiently certainly obtainable. Adult stem cells can also proliferate and migrate to the site of injury fast then inhabit and start regenerating the tissue or organ, and within days the progression and new cell count can be measured (Elad, 2014).Stem Cell Treatments for Cancer Essay.
On the other hand, the collection of the required number of stem cells in peripheral blood and cord blood stem cell transplantations is somehow difficult. The procedures of collecting peripheral blood stem cells is generally more convenient for both donor and doctors as it can be done in an outpatient settings and does not involve general anesthesia; however, the number of stem cells collected will, in most cases, be lower than that obtained from bone marrow and therefore the procedure might multiple donations to be done over a number of days until enough stem cells are collected for a single patient (Habib, 2006).
Moreover, the number of hematopoietic stem cells is, to a large extent, difficult to amplify because they tend to divide asymmetrically and may in turn result in increased risk of developing genetic instability. Another downfall includes the early complications that are likely to be experienced by the stem cell recipient such as nausea and vomiting, and may lead to further complications as in cases mucositis and interstitial pneumonitis. They can also result in bacterial infections and the development of graft-versus-host disease (Habib, 2006).Stem Cell Treatments for Cancer Essay.

3.5. Donor Matching:
Autologous stem cell transplants do not require any type of matching tests because the stem cells collected are originated from the patients’ own body before being diseased (Ji, 2003).
However, in the case of allogeneic transplants, and as the stem cells to be transplanted come from a donor, tissue type match between the donor and recipient has to be close. Otherwise, the recipient’s immune system will recognize the stem cells transplanted as foreign bodies and destroy them, this process is called “ Graft rejection”, and this is a rare case when the donor and recipients are well matched. Another issue that may arise when stem cells are transplanted is when the donors stem cells make their own immune cells, the new cells transplanted may recognize the recipients’ cells as foreign and turn against their new home, this is known as “graft-versus-host disease”. This is the most important reason to find the closest match possible before transplants take place (Hough, 2009).

HLA Matching:
The ability of the immune system to know the difference between which cells belong to the body and which do not is based on many factors, and the most important factor is the Human Leukocyte Antigen (HLA) system. HLA are proteins found on the surface of most cells, they make up the tissue type for a person, which is different from a persons blood type. Each person has a number of pairs of HLA antigens; these antigens are passed from parents to their children, taking a single HLA antigen from each parent resulting in pairs of HLA for each child (Ji, 2003).Stem Cell Treatments for Cancer Essay.
Back to stem cell transplantation, the HLA match between the donor and recipient plays a very important role in the success of the transplant, if fact, HLA matching is the key factor to guarantee the completion and achievement of successful transplants. HLA has six major antigens, and the matching tests for all the six antigens to determine how close that match will be. The perfect match is when all the six HLA antigens are matched between the donor and the recipient. Stem cell transplantations with perfects matches have much lower chances of complications such as graft rejection, graft-versus-host disease, developing a weak immune system and serious infections (Couri, 2012).Stem Cell Treatments for Cancer Essay.

3.6. After Treatment, and Vaccines:
3.6.1. Engraftment and Preventing Infections:
During the first 2-3 weeks after transplantation, the re-infused cells migrate to the bone marrow and start diving and producing new blood cells. This process is called “engraftment” and it is said to be successful once the body has accepted the new stem cells and started manufacturing new blood cells (Figuerres, 2000).
From the time of infusing and until the time of engraftment, the patient is very vulnerable to developing infections. Due to the high-dose chemotherapy the patients’ immune system is very weakened in a way that a minor cold or flu could be transmitted to the patients causing them serious infection problems (Figuerres, 2000). Patients are usually instructed to follow a certain procedure after transplantation to curb any chance of being infected. These instructions may include: prescription of antibiotics, banning fresh fruits, vegetables and flowers from their surroundings as they may be carriers to bacteria or fungi, and visitors should be wearing gloves, gowns and masks for the protection of patients (Ovayolu, 2013).Stem Cell Treatments for Cancer Essay.

3.6.2. Vaccination:
Vaccinations for Streptococcus pneumonia and Haemophilus influenza are recommended for all stem cell transplants recipients. Inactivated vaccine injections should be used for family members who need vaccination against polio, and isolation is necessary if oral polio vaccine is administered to any member who has close contact with the patient during the first year after transplant (Lodi, 2011).
Live vaccines, such as live attenuated influenza vaccine, smallpox vaccine and any other vaccine containing live vaccinia virus, is contraindicated is hematopoietic stem cell transplantation recipients because it may result in the development of generalized vaccinia or inadvertent inoculations at other site such as the face, eyelid, nose, mouth, genitals, and rectum (Lodi, 2011).
For certain high risk groups undergoing high-dose chemotherapy, Anthrax vaccine is highly recommended as it has no dead or live bacteria, it is an inactivated cell-free filtrate vaccine (Elad, 2014).

3.7. Mechanisms of Mobilization:
The term “Mobilization” is defined as the process of which hematopoietic and progenitor cells are employed to the blood following chemotherapy. This process acts the same way as the physiological release of stem cells from their reservoir in response to stress signals during injury or inflammation (Angelopoulou, 2014). Currently, the mobilization of hematopoietic and progenitor cells is the most commonly used method is stem cell transplantation because the stem cells are usually harvested from either peripheral of cord blood resulting in higher yield, faster engraftment, and decreased procedural risk. Stem cell mobilization involves the introduction of physiological interplay between mesenchymal stromal and hematopoietic cells regulating both bone and bone marrow remodeling process, which in turn mediates stem cell division, proliferation and migration (Angelopoulou, 2014).
The process of mobilization is initiated by the activation of neutrophils and osteoclasts by stress induced activation when receiving chemotherapy. Increased cell release from the bone marrow reservoir is part of the immune system host defense during inflammation that is caused by injury or infection (Angelopoulou, 2014).Stem Cell Treatments for Cancer Essay.
There is a number of methods for the mobilization of stem cells, each methods has its own factors that affect the way stem cells are mobilized, the yield they result in, and the side effects they might cause the patients to have (Angelopoulou, 2014).
According to Angelopoulou in 2014, the most commonly used method of mobilizing stem cells is by using Granulocyte Colony-Stimulated Factor (G-CSF) as a standard physiological agent and sometimes in combination with other agents. For patients with Non-Hodgkin Lymphoma, it is recommended to use steady-state mobilization with G-CSF alone due to its low toxicity, although its failure rate might be higher in some cases. Chemo-Mobilization, or CM, is also appropriate method of mobilization whether it is incorporated into the initial 3-6 cycles of chemotherapy or as a part of a salvage regimen.Stem Cell Treatments for Cancer Essay.
However, the debate on whether the best approach is to mobilize stem cells with Growth Factors, G-CSF or CM or a combination of G-CSF and CM method is not over and has yet to be determined (Angelopoulou, 2014).Stem Cell Treatments for Cancer Essay.

3.9. Preservation of Umbilical Cord Blood Stem Cells and Its Cost:
After the collection of umbilical cord blood stem cells and until they are needed for a transplant, the plasma, and sometimes RBCs, is removed from cord blood and then the stem cells are stored at very low temperatures of liquid nitrogen vapor phase. Although the lifetime of stem cells while being stored has not been fully determined, scientists believe that it would definitely be more than 20 years of storing as more than 99% of stored stem cells that have not been used within 20 years remained viable (Zimmerman, 2015). Most transplant experts suggest that umbilical cord blood stem cells may remain viable indefinitely. The cost of storing stem cells is approximately $150 U.S.D. paid on annual basis along the period of storing (Stemcyte, 2016).Stem Cell Treatments for Cancer Essay.

3.9. Clinical Applications of Stem Cell Transplantation:
In the last two decades, the interest of stem cell research has increased dramatically not only for the medical and scientific community, but also among religious groups, politicians and ethnicities. Human stem cells are being utilized in a number of therapeutic procedures and, as they have the ability to transform to many cell types, they are being studied on large scales to treat different types of cancers, infections and chronic diseases (Habib, 2006).
Stem cell transplantation has shown outstanding improvements in curing many diseases such as the treatment of cardiovascular diseases, multiple sclerosis (MS), leukemia, and lymphoma (Harris, 2013).Stem Cell Treatments for Cancer Essay.

3.8.1. Cardiovascular Repair:
Q. Sun in 2014 stated that the addition of myeloid derivatives as donor cells to hematopoietic stem cells might provide more effective cell-based therapy for cardiac repair. The hint here is using hematopoietic stem cells in cardiovascular repair implies that they are likely to achieve the goals required for stem cell transplant. However, their low frequencies, difficult maintenance in cell culture, and the unknown signaling pathways that control the proliferation and differentiation of stem cells should be further studied. Nevertheless, specific induction of hematopoietic stem cells into cardiomyocytes must be generated to avoid tumor genesis.
3.8.2.Multiple Sclerosis (MS):Stem Cell Treatments for Cancer Essay.
Stem cell transplantation could help in treating MS by two processes; Immunomodulation or Remyelination. Immunomidulation method works by preventing immune damage to the nervous system, to maintain its fully functionality and stop damaging the myelin sheath that causes the relapses of MS in first place (Tesar, 2015).
The Remyelination process takes place in a way that stem cells are capable of repairing the myelin sheath that has already been damaged by promoting the nervous systems’ own mechanisms of repair to deal and repair the damaged sheath (Tesar, 2015).Stem Cell Treatments for Cancer Essay.

3.8.3. Leukemia:
Studies have shown that allogeneic transplantations have the ability to cure patients with leukemia but the risks are significant due to the high toxicity when cellular immune therapy is used in combination with chemotherapy (Lekakis, 2008).Stem Cell Treatments for Cancer Essay.
3.8.4. Lymphoma:
Stem cell transplants aim to improve the quality of life of patients, prolong remission and eventually cure lymphoma. Stem cell transplantation can be used for patients who have already undergone earlier courses of treatment, for those who failed to respond to treatment, or to prolong remission for patients who are likely to be at higher risk of relapse (Ritchie, 2008).
Most lymphoma patients treated with stem cell transplants are those with Hodgkin lymphoma or higher-grade non-Hodgkin lymphoma who have relapsed after the first course of treatment. The goal of such procedures in this context is to provide prolonged remission as a start, and then cure the lymphoma if possible (Angelopoulou, 2014).Stem Cell Treatments for Cancer Essay.

4. Methods:
A questionnaire consisted of eight questions was constructed using Survey Monkey Online Application that targeted public participants. The questionnaire was collected and analyzed from 100 participants.

5. Results:
When participants were asked to evaluate their knowledge of Stem Cell Transplants, 8% stated they had full knowledge about the procedure, 54% had a simple knowledge, and 34% had no knowledge at all as shown in figure 1.Stem Cell Treatments for Cancer Essay.

Figure1: General Perception of Stem Cell Transplantation.

When participants were asked about their ability to identify all or some of the sites of which stem cells can be collected from, the results of whether participants can fully identify them, they can identify some places where stem cells are obtained from, or whether they cannot identify a single site at all were 10%, 42%, and 48%, respectively, as shown in figure 2.Stem Cell Treatments for Cancer Essay.

Figure 2: The ability to identify sites of collection of stem cells.
The figure below shows the responses of subjects when they were asked a Yes or No question about knowing the uses of stem cell transplantation.

Figure 3: knowledge about the clinical applications of stem cells.

Question number four aimed to evaluate participants’ knowledge about the therapeutic uses of stem cell transplantation for some cancer types. 7% of participants are aware of the role of stem cell transplants in cancer, 47% had limited understanding of the role, and 46% were unaware of the role of stem cells in cancer therapy.Stem Cell Treatments for Cancer Essay.

Figure 4: Awareness of the role of stem cell transplants for the therapy of some cancer types.
Participants’ responses to whether such procedures are used in hospitals in Saudi Arabia were as follows; 40% answered that the procedure is being carried out in Saudi hospitals, 23% think stem cell transplantation procedures are not available in Saudi Arabia, and 37% remained neutral and did not follow into neither categories below.Stem Cell Treatments for Cancer Essay.

Figure 5: The application of stem cell transplants in hospitals in Saudi Arabia.

The responses on whether the addition of stem cell transplants is more effective than chemotherapy and other pharmacologic modalities in the treatment of cancers or other diseases have show promising trust in future applications of stem cell transplants. The largest portion of participants, 50%, stated that the addition of SCT to chemotherapy do enhance the outcomes of cancer therapy. On the hand, 9% disagreed that it would be better if used in combination with chemotherapy, and 41% had no impression and remained neutral.Stem Cell Treatments for Cancer Essay.

Figure 6: SCT is a more effective approach in treating diseases.

In addition, most of participants were optimists and agreed that stem cell transplantation has the ability to cure many diseases in future, with the 58 percent, while only 4% responded that it would not make a difference. The remaining 38% stayed neutral, as shown in figure 7.Stem Cell Treatments for Cancer Essay.

Figure 7: Stem cell transplants are capable of treating many diseases in future.

The majority of participants stated that they would save stem cells for their children in future if they had the chance of doing so. On the other hand, 44% stated that they would not save stem cells.Stem Cell Treatments for Cancer Essay.

Figure 8: Will save stem cells for your children in future for, God forbid, if they might need SCT?

6. Discussion and Limitations:
The results of the study revealed that, despite the lack of public awareness assumed, the majority of the public had some knowledge regarding stem cell transplants. This could be due to the expanding number of applications of such procedure and the contribution of the media to such breakthroughs. The largest portion of participants were unable of identifying sources of stem cell harvesting, which is suggestive of the mere understanding of the concept on stem cell transplantation by the public. A small number however, was able to point all the sources of adult stem cell.Stem Cell Treatments for Cancer Essay.
When participants were asked about the clinical applications of stem cells, most of them were not familiar with the exact contribution of the intervention, but knew that it assists in the treatment of some diseases. The remaining portion of participants knew some contributions of SCTs in therapeutic applications.
The role of SCTs in cancer therapy was recognized by a very small number of subjects, a larger number understood the concept that SCTs assist in treating cancer, but did not know how it would exactly contribute to the treatment. Being aware of such procedures may have been caused by the increased and more frequent SCTs done over the last decade, or because those participants have had a glimpse of the approaches of SCTs.Stem Cell Treatments for Cancer Essay.
More than two thirds of participants, 40%, believe that stem cell procedures are bring carried out in Saudi Arabia, their stand might be due to a personal experience of such intervention, or some of their relatives, or people they know, have undergone SCTs in Saudi Arabia. On the other hand, 23% stated that such procedures are not available in Saudi hospitals, and that such advances in medical therapy will take sometime before they are implemented and applied in a developing country health system.
According to 50% of participants, the application of SCTs is more effective than other modalities in treating some diseases, while only 9% said it was not, and the remaining 41% could not judge the efficacy of the intervention. When participants were to evaluate the future improvements of SCT applications, the largest group agreed that it would definitely enhance the treatment of diseases in the future, where the second largest group argued that stem cell transplantations would not be of much help in future. The smallest portion of participants disagreed that it would improve treating diseases.Stem Cell Treatments for Cancer Essay.
When participants were asked about whether they would save stem cells for their children, the idea had acceptance of the majority of participants, but the other group stated that saving stem cells for their children is not worthy of either the process of harvesting stem cells nor the cost of the saving.Stem Cell Treatments for Cancer Essay.
The limitations of the study included the poor generalization of public awareness regarding stem cell transplantations due to the low number of participants the data was collected from. Time limit of conducting the research is believed to result in better sampling of participants if it had been longer. Nonetheless, the research should have included samples of cancer patients and oncologists to better evaluate whether cancer patients are informed about the contribution of stem cell transplants in treating cancers along the course of the other therapeutic modalities such as chemotherapy and radiation therapy.Stem Cell Treatments for Cancer Essay.

7. Conclusion:
Yet the concept of stem cell transplantations and its role to help in treating cancer are ill-defined in Saudi Arabia, the majority of the public do have perception about stem cells but not the extend of prolonging the remission and treating cancer. Hence, the need to raise public awareness regarding stem cell transplantation, its contribution and role in treating and preventing the relapses of cancers is definitely demanded by the health system. The uses of SCTs in treating other diseases such as Multiple Sclerosis and Cardiovascular repair should also be outlined in stem cell transplantation awareness-raising campaigns.Stem Cell Treatments for Cancer Essay.

The expression of markers of cellular senescence increases exponentially in multiple tissues with aging. Age-related physiological changes may contribute to adverse outcomes in cancer survivors. To investigate the impact of high dose chemotherapy and stem cell transplantation on senescence markers in vivo, we collected blood and clinical data from a cohort of 63 patients undergoing hematopoietic cell transplantation.Stem Cell Treatments for Cancer Essay. The expression of p16INK4a, a well-established senescence marker, was determined in T-cells before and 6 months after transplant. RNA sequencing was performed on paired samples from 8 patients pre- and post-cancer therapy. In patients undergoing allogeneic transplant, higher pre-transplant p16INK4a expression was associated with a greater number of prior cycles of chemotherapy received (p = 0.003), prior autologous transplantation (p = 0.01) and prior exposure to alkylating agents (p = 0.01). Transplantation was associated with a marked increase in p16INK4a expression 6 months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4a expression (3.1-fold increase, p = 0.002) than allogeneic transplant recipients (1.9-fold increase, p = 0.0004). RNA sequencing of T-cells pre- and post- autologous transplant or cytotoxic chemotherapy demonstrated increased expression of transcripts associated with cellular senescence and physiological aging. Cytotoxic chemotherapy, especially alkylating agents, and stem cell transplantation strongly accelerate expression of a biomarker of molecular aging in T-cells.Stem Cell Treatments for Cancer Essay.

Keywords: Aging, Senescence, Exhaustion
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1. Introduction
Hematopoietic stem cell transplantation (HSCT) is a potentially curative modality for high-risk hematologic diseases, but the procedure has profound and long-term effects on recipient hematologic and immune function. The long-term toxicity of HSCT may result from chemo-radiotherapy given at the time of transplantation (conditioning), from donor-host immune differences after allogeneic transplants or from accelerated stem cell exhaustion of transplanted stem cells (Hake et al., 2007). These late toxicities manifest as increased risk for infection, chronic graft-vs-host disease, bone marrow failure and acute leukemia.Stem Cell Treatments for Cancer Essay.

Recent evidence has demonstrated that peripheral blood T-cells express markers of cellular senescence with physiological aging. The overall loss of physiological reserve that accompanies aging is associated with an accumulation of senescent cells (Sharpless and Depinho, 2007, Rodier and Campisi, 2011). Cellular senescence is triggered by activation of tumor suppressor mechanisms associated with cellular stressors, and results in expression of the p16INK4a tumor suppressor protein encoded by the CDKN2a locus, which has emerged as one of the more useful markers of senescence in vivo (Campisi, 2013, Sharpless and Sherr, 2015).Stem Cell Treatments for Cancer Essay. Expression of p16INK4a in peripheral blood T lymphocytes increases exponentially with chronological age, doubling about every decade (Zindy et al., 1997, Krishnamurthy et al., 2004, Liu et al., 2009). Polymorphisms of senescence regulators have been associated with age-related conditions such as cancer, pulmonary fibrosis, glaucoma, atherosclerosis, and type II diabetes (Jeck et al., 2012, Siegel et al., 2012). Prior work has shown that several age-promoting stressors such as smoking, physical inactivity and chronic HIV infection accelerate the expression of p16INK4a and other markers of cellular senescence (Liu et al., 2009, Nelson et al., 2012). Importantly, we recently showed that cytotoxic chemotherapy, given in the adjuvant setting, markedly increases expression of senescence markers in the peripheral blood, consistent with ~ 15 years of chronological aging (Sanoff et al., 2014).Stem Cell Treatments for Cancer Essay.

Increasingly, older individuals are considered for autologous or allogeneic transplantation. While age itself is usually not considered an absolute contraindication to transplantation, older individuals do have higher risks of acute transplant-related toxicities such as cardiac arrhythmias, diarrhea and mucositis (Wildes et al., 2014). Further, age-related comorbid illness is itself prognostic for outcomes in autologous and allogeneic transplant recipients, suggesting that functional, if not chronological, age of prospective transplant candidates is a potentially important variable for clinical decision-making. Lastly, survivors of transplants, regardless of age, are at risk for accelerated acquisition of several age-related syndromes such as endocrine dysfunction, cognitive impairment, cardiovascular morbidity, immune dysfunction, secondary neoplasms, and neuromuscular impairment (Fried et al., 2001).Stem Cell Treatments for Cancer Essay.

In murine models, serial transplantation per se, in the absence of exposure to cytotoxic agents, is associated with accelerated aging of hematopoietic stem cells (HSC), manifesting as ‘HSC exhaustion’ (Harrison and Astle, 1982). Likewise, evidence suggests HSC exhaustion occurs in humans as well. HSC yields for autologous transplant from patients that have undergone significant prior chemotherapy are significantly depressed compared to yields from less heavily treated individuals (Clark and Brammer, 1998), and the transplantation of insufficient numbers of HSC is associated with long term graft failure (Perez-Simon et al., 1999). Additionally, transplantation is associated with an increased rate of telomere shortening, which has been associated with certain adverse outcomes in transplant recipients (Lee et al., 1999, Lewis et al., 2004, Akiyama et al., 2000, Pipes et al., 2006). Because individuals with hematologic malignancies have an increasing array of transplant approaches of varying intensity as well as non-transplant treatment approaches available to them, understanding the impact of treatment upon functional aging may have important implications for the care of both prospective transplant candidates as well as transplant survivors. Toward that end, we measured expression of p16INK4a, a marker of molecular age that can be serially assessed, in HSC-derived T-cells before and after stem cell transplantation. Additionally, we performed whole transcriptomic RNA sequencing in a subset of paired samples to further examine the effects of chemotherapy or transplantation on T-cell function.Stem Cell Treatments for Cancer Essay.

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2. Materials and Methods
2.1. Patients
For the transplant patient population, participants were over the age of 18 and underwent either autologous or allogeneic stem cell transplantation for any hematologic malignancy between 2010 and 2013 at the University of North Carolina (UNC) Hospitals. Patient samples were obtained from two non-randomized, non-blinded observational cohorts: a study investigating symptom burden after transplantation, and a generic tissue procurement protocol. Studies were approved by the UNC Institutional Review Board (11–0600 and 13–1705), with study procedures confirming to standards indicated by the Declaration of Helsinki. Eligible patients were identified from the electronic medical records and approached by research personnel prior to scheduled transplantation for provision of signed informed consent.Stem Cell Treatments for Cancer Essay. Patients undergoing concurrent radiation, chemotherapeutic, or investigational therapy other than transplant-related therapy were excluded. All patients received standard-of-care therapies and treatments as clinically needed. Medical history and treatment information were abstracted from the medical record. Samples were obtained in both cohorts from just before transplantation, and paired samples from 6 months post-transplantation were also obtained if available. Molecular analyses were performed by investigators blinded to patient data, and investigators collecting clinical information were blinded to laboratory results until data collection was complete. For the breast cancer patient population, T-cell RNA collected in the study Sanoff et al. (Sanoff et al., 2014) was used in the RNA sequencing analysis.Stem Cell Treatments for Cancer Essay.

2.2. Assessment of p16INK4a expression
See Sanoff et al. (Sanoff et al., 2014) for details. In brief, CD3+ T-cells were isolated from up to 10-ml of peripheral blood using anti-CD3 microbeads and an AutoMACSPRO separator (Miltenyi Biotec, San Diego, CA). Purity of T cells was determined to be ~ 95% when isolated from fresh blood and ~ 50% when isolated from cryopreserved PBMCs in pilot experiments. T cell purity in clinical trial samples was monitored by measuring expression of the gamma subunit of the CD3. Total RNA was isolated using RNeasy Mini Kit (Qiagen) and cDNA were prepared using ImProm-II reverse transcriptase kit (Promega). Expression of p16INK4a was measured by TaqMan quantitative reverse-transcription polymerase chain reaction specific for p16INK4a and normalized to YWHAZ housekeeping gene (Mane et al., 2008, Dheda et al., 2004).Stem Cell Treatments for Cancer Essay.

2.3. RNA Sequencing
RNA was extracted and rRNA was removed using the Ribo-Zero kit. RNA libraries were prepared by using the Illumina TruSeq RNA Sample Preparation Kit v2 and then sequenced by Illumina HiSeq2000. Reads were subjected to quality control as previously described (Cancer Genome Atlas Research, 2012). RNA reads were aligned to human hg19 genome assembly using Mapsplice (Wang et al., 2010). Gene definitions were obtained from the UCSC known Gene table. Gene expression was estimated using RSEM (RNA-Seq by Expectation Maximization) (Li and Dewey, 2011). Genes differentially expressed due to treatment were identified by DESeq2 (Love et al., 2014) using a bivariate model to adjust for subject specific effects. The resulting statistics were subjected to gene set enrichment analysis by using the GSEA (Gene Set Enrichment Analysis) rank test (Subramanian et al., 2005). Expression estimates were normalized to a fixed upper quartile and log2 transformed prior to visualization.Stem Cell Treatments for Cancer Essay.

2.4. Statistical Analyses
The sample size was determined by the availability of clinical specimens from the two study cohorts as described. Log2-transformed p16INK4a expression values were standardized through conversion to Z-score to facilitate combining the two sample sets. Z-scores were calculated separately for the two transplant cohorts using the formula:

Zi = (Xi − μ)/σ
where μ is population mean, and σ is standard deviation.

For samples present in both cohorts, individual Z scores were averaged. Associations between p16INK4a expression and pre-transplant variables were performed using linear regression (for continuous variables) or one-way analysis of variance (for categorical variables). A paired t-test was used to compare p16INK4a expression before and after transplant. Data were analyzed by N. Mitin using JMP11 (SAS, Cary, NC) and A. Snavely using R. All tests of statistical significance were two-sided. P values of 0.05 or less were considered statistically significant.Stem Cell Treatments for Cancer Essay.

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3. Results
Two observational cohorts (Table 1) were combined for our analysis, and the baseline characteristics of the aggregated cohort are shown in Table 2. In order to compare samples analyzed from the two observational cohorts, we converted all p16INK4a expression values to a normalized Z-score as described in the methods. Using this conversion, we found excellent correlation among Z-scores for the 17 patients that had separate samples obtained in both cohorts (Table 3), suggesting the aggregation of the observational cohorts for analysis is valid. In the combined cohort there were 26 unique patients who underwent autologous transplantation and 37 who underwent allogeneic transplantation, for a total of 63 unique patients (Table 2). A majority of autologous transplant recipients had myeloma, and the rest had lymphoma as an underlying diagnosis. Most allogeneic transplant recipients had leukemia as their underlying diagnosis. Five allogeneic transplant recipients had previously undergone autologous transplantation.Stem Cell Treatments for Cancer Essay.

Table 1
Summary of clinical samples used in this study.

Number of samples
Symptom burden observational studya
Baseline samples 28
Autologous transplant 8
Allogeneic transplant 20
6-month follow up samples 16
Autologous transplant 5
Allogeneic transplant 11
Tissue procurement observational study
Baseline samples 35
Autologous transplant 18
Allogeneic transplant 17
6-month follow up samples 11
Autologous transplant 1
Allogeneic transplant 10
a17 patients participating in the symptom burden study also had specimens stored in the tissue procurement facility and collected in the second cohort. In all, 21 samples were shared between the two cohorts- 17 baseline samples and four 6-month follow-up samples. These samples are not counted in the second cohort summary table above.Stem Cell Treatments for Cancer Essay.
Table 2
Baseline characteristics of hematopoietic stem cell transplantation (HSCT) patients in this study.

Characteristic Autologous HSCT Allogeneic HSCT Total
N 26 37 63
Age (mean (SD)) 59.0 (8.6) 54.2 (11.4) 56.2 (10.5)
Male 15 (58%) 24 (65%) 39 (62%)
Female 11 (42%) 13 (35%) 24 (38%)
Caucasian 24 (92%) 30 (81%) 54 (86%)
Myeloma 14 (54%) 1 (3%) 15 (24%)
Lymphoma 10 (38%) 4 (11%) 14 (22%)
Acute leukemia 0 19 (51%) 19 (30%)
Prior treatments
Chemotherapy exposure in months (mean (SD)) 6.6 (5.2) 7.2 (10.2) 7.0 (8.5)
Number of chemotherapy regimens (mean (SD)) 1.9 (1.2) 2.4 (1.7) 2.2 (1.5)
Number of chemotherapy cycles (mean (SD)) 8.0 (5.2) 5.9 (5.0) 6.8 (5.1)
Anthracycline 13 (50%) 22 (59%) 35 (56%)
Nucleoside analogue 4 (15%) 22 (59%) 26 (41%)
Lenalidomide or thalidomide 14 (54%) 2 (5%) 16 (25%)
Bortezomib 12 (46%) 0 12 (19%)
Prior Autologous transplant 1 (4%) 4 (11%) 5 (8%)
Comorbidity score (HCT-CI) (mean (SD)) 3.7 (2.8) 2.7 (2.0) 3.1 (2.4)
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Table 3
Comparison of p16INK4a expression levels in T cells isolated from fresh blood (symptom burden cohort (SB)) or frozen PBMCs (tissue procurement cohort (TP)). A Z score was calculated for samples in each cohort and the values of 20 samples shared between cohorts is shown (r2 = 0.6).Stem Cell Treatments for Cancer Essay.

p16_SB p16_TP
A101 1.83 0.34
A103 − 1.34 − 1.40
A108 6 months − 0.33 0.14
A108 BL − 0.74 − 1.94
A109 6 months 0.44 0.68
A109 BL − 1.52 − 1.04
A110 − 1.59 − 0.50
A202 − 0.50 − 0.96
A203 0.52 − 0.05
A204 0.13 1.39
A208 6 months 1.55 1.90
A208 BL − 0.63 − 1.17
B202 6 months − 0.39 0.65
B202 BL − 0.61 − 0.54
B204 − 1.32 − 1.45
B205 0.06 − 0.38
B206 0.94 2.05
B209 − 0.63 − 0.26
B211 1.61 1.27
B212 − 0.11 − 0.28
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Among autologous HSCT recipients, there were no baseline characteristics that were associated with pre-transplant p16INK4a expression. Among allogeneic HSCT recipients, however, a greater number of cycles of chemotherapy received before allogeneic transplant, history of prior autologous transplantation, and history of alkylating agent exposure were all significantly associated with higher pre-transplant p16INK4a expression (p < 0.01 for each, Table 4A and B). In accord with results in patients treated with chemotherapy for breast cancer (Sanoff et al., 2014), prior exposure to alkylating agents was associated with a 1.9-fold increase in p16INK4a expression (absolute value, log2 = 0.91). Moreover, there was a 2.3-fold increase in p16INK4a expression level (absolute value, log2 = 1.22) in the small number of allogeneic patients that had undergone prior autologous transplant. Previously, we have shown that a 2-fold increase in p16INK4a expression is equivalent to ~ 10 years of chronological aging (Sanoff et al., 2014). Therefore, these data suggest that extensive exposure to alkylating agents or autologous transplantation is equivalent in molecular terms to a chronological decade or more increase in the chronological age of Peripheral Blood T-Lymphocytes (PBTL).Stem Cell Treatments for Cancer Essay.

Table 4
Pre-transplant p16INK4a expression is associated with amount and type of pre-transplant chemotherapy and history of prior autologous transplant in univariate analysis. Linear regression analysis (A) and one-way analysis of variance (B) demonstrate association of p16INK4a with patient’s characteristics and therapies.Stem Cell Treatments for Cancer Essay.

Baseline characteristic Autologous HSCT (N = 26)
Allogeneic HSCT (N = 37)
Estimate (log 2) p-Value Estimate (log 2) p-Value
Age − 0.002 0.94 0.001 0.92
Comorbidity score (HCT-CI) − 0.081 0.18 − 0.40 0.60
Number of cycles of chemotherapy 0.014 0.68 0.086 0.003

Baseline characteristic Autologous HSCT (N = 26)
Allogeneic HSCT (N = 37)
Difference (log 2) p-Value Difference (log 2) p-Value
Prior autologous transplant NA NA 1.22 0.01
Exposure to alkylator – incl prior auto 0.20 0.56 0.91 0.01
Exposure to alkylator – not incl prior auto 0.19 0.6 0.62 0.13
Exposure to anthracycline 0.28 0.41 − 0.04 0.91
Exposure to nucleoside analogue 0.70 0.13 − 0.23 0.45
Exposure to lenalidomide or thalidomide − 0.04 0.91 0.75 0.26
Exposure to bortezomib 0.05 0.88 NA NA
Next, we determined the effects of HSCT on molecular age of PBTL as measured by p16INK4a expression by comparing pre- and post-HSCT p16INK4a levels within an individual. As shown in Table 5, hematopoietic stem cell transplantation was associated with a significant increase in p16INK4a expression levels for both autologous and allogeneic transplant recipients. Allogeneic transplant recipients showed a pronounced increase in p16INK4a expression post-HSCT (1.93-fold, p = 0.0004). In the allogeneic setting, the PBTL pre-HSCT were derived from the host, whereas the PBTL post-HSCT were largely if not entirely donor-derived (given near 100% chimerism in patients post-engraftment). Since the hosts, who generally were transplanted for AML, had experienced prior chemotherapy and, in a small number of cases, auto-HSCT, we would expect that the pre-HSCT levels of p16INK4a would be considerably higher than the expression of p16INK4a in their healthy donors. Therefore, the measured change in p16INK4a from pre-HSCT to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects on the graft of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure. In the allogeneic HSCT setting, it is possible that other unaccounted factors (e.g. post-transplant calcineurin-inhibitor exposure) may have also contributed to the observed effect.Stem Cell Treatments for Cancer Essay.

Table 5
High-dose chemotherapy increases p16INK4a expression. Changes in p16INK4a expression between baseline and follow-up in aggregated cohort in autologous-HSCT, allogeneic-HSCT or breast cancer patients.

Treatment type Pre-treatment log2p16 Post-treatment log2p16 Change in p16INK4a expression P-value
Autologous HSCT (mean (95% CI)); N = 6 − 0.88 (− 1.44, − 0.32) 0.73 (0.20, 1.27) 3.05 0.002
Allogeneic HSCT (mean (95% CI)); N = 21 − 0.13 (− 0.53, 0.27) 0.82 (0.53, 1.11) 1.93 0.0004
Adjuvant breast cancer (mean (95% CI); N = 24 − 0.48 (− 0.12, − 0.83) 0.48 (0.22, 0.74) 1.93 0.0001
In order to directly measure the effects of human HSCT per se on molecular age, we turned to an analysis of patients undergoing autologous HSCT. In accord with our finding that autologous HSCT prior to allogeneic transplant was associated with elevated p16INK4a in pooled patients (Table 4), we noted that within any given patient, autologous HSCT was associated with a marked increase in p16INK4a expression from pre-transplant to 6 months post-transplant (3.05-fold, p = 0.002). This finding suggests that the forced bone marrow repopulation associated with transplantation per se accelerates the molecular aging of PBTL, in the absence of significant chemotherapy exposure to the graft.Stem Cell Treatments for Cancer Essay.

3.1. Relationship of Transplantation and Chemotherapy with Peripheral Blood T-cell Gene Expression
To further understand the long-term effects of DNA damaging agents and HSCT on PBTL, we performed whole transcriptome RNA sequencing before and after cancer therapy. In order to identify transcriptional changes that were not specific to a particular noxious insult, but instead were induced by the generic insult of forced bone marrow regeneration, we performed an analysis of samples pre- and post-autologous transplantation (3 pairs of samples) or pre- and post-cytotoxic chemotherapy (5 pairs of samples). In order to focus on durable changes to the T-cell transcriptome, PBTL were collected 6 months post-autologous HSCT or 6–12 months post-adjuvant chemotherapy with doxorubicin and cyclophosphamide for breast cancer (these samples are described in (Sanoff et al., 2014)). We performed whole transcriptome RNA sequencing of ribosome depleted total RNA on pre- and post-therapy T-cell samples, and compared expression profiles through pairwise supervised analysis. This approach identified a signature of ~ 500 coding transcripts whose expression was significantly (adjusted p-value < 0.05) and durably altered by these types of cancer therapy. If restricted to genes whose expression changed > 1.9-fold from baseline, we identified 134 coding transcripts that significantly increased in expression, and 47 transcripts that significantly decreased in expression (Supp. Tables 1, 2), which are presented as a representative subset in Fig. 1 and overall by hierarchical clustering in Fig. 2. These data demonstrate a potent and lasting effect on transcription of the T-cell organ after forced bone marrow regeneration.Stem Cell Treatments for Cancer Essay.

Fig. 1
Fig. 1
A hierarchical clustering of representative transcripts whose expression significantly changes with cancer therapy (3 pair of auto-HSCT samples or 5 pair of chemotherapy-treated samples) in peripheral blood T-cells (CD3 +). Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Genes of interest are ordered along the y-axis as described in the Results section, with color-coding indicated to the left of the heatmap (purple = senescence associated; light blue = telomere shortening; brown = effector; yellow = NK; orange = exhaustion). Sample numbers are shown below the heatmap, with an “A” prior to sample numbers indicating patients undergoing auto-HSCT. Samples without an “A” indicate patients treated with chemotherapy and not transplantation. Samples are ordered along the x-axis.Stem Cell Treatments for Cancer Essay.

Fig. 2
Fig. 2
A hierarchical clustering of all transcripts whose expression significantly changes with cancer therapy (3 pair of auto-HSCT samples or 5 pair of chemotherapy-treated samples) in peripheral blood T-cells (CD3 +). Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Sample numbers are shown below the heatmap, with an “A” prior to sample numbers indicating patients undergoing auto-HSCT. Samples without an “A” indicate patients treated with chemotherapy and not transplantation. Samples are ordered along the x-axis as in Fig. 1.Stem Cell Treatments for Cancer Essay.

In order to determine the effects of auto-transplant or chemotherapy on T-cell function, we performed several types of bioinformatic analysis on these RNA sequencing data. We used gene set enrichment analysis (GSEA) and supervised gene set analysis (SAM-GSA) to compare the genes altered by cancer therapy to ~ 8000 known gene sets in the Molecular Signatures database (Subramanian et al., 2005). These analyses identified a large number of published signatures with significant overlap with our gene list, of which the vast majority (> 90%) were immunologic. Using an adjusted p-value of 0.05, 211 gene sets significantly overlapped with transcripts more highly expressed in the pre-therapy samples (Supp. Table 3), and 98 overlapped with transcripts that were more highly expressed in the post-therapy samples (Supp. Table 4). Hierarchical clustering of representative GSEA signatures are shown in Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7. These GSEA results appear to be predominantly explained by changes in the composition of the CD3 + fraction of lymphocytes post-cancer therapy. For example, transcripts that were more highly expressed in memory CD4 + cells relative to naïve cells increased after cancer therapy (Fig. 3), and the same was true for transcripts that were more highly expressed in effector memory compared to central memory CD4 + cells (Fig. 4). Transcripts that were more highly expressed in regulatory T cells compared to conventional T cells also increased following cancer treatment (Fig. 5). As shifts from central memory and naïve cells to effector cells and Tregs are hallmark changes of peripheral T-cells with aging (Desai et al., 2010), these data provide further evidence that cancer therapy accelerates the changes in T-cell subsets that are associated with aging of the cellular immune system.Stem Cell Treatments for Cancer Essay.

Fig. 3
Fig. 3
A hierarchical clustering of transcripts from a Gene Set Enrichment Analysis Signature (GSE11057) with increased expression in memory CD4 + cells compared to naïve cells. Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Sample numbers are shown below the heatmap, with an “A” prior to sample numbers indicating patients undergoing auto-HSCT. Samples without an “A” indicate patients treated with chemotherapy and not transplantation. Samples are ordered along the x-axis as in Fig. 1.

Fig. 4
Fig. 4
A hierarchical clustering of transcripts from a Gene Set Enrichment Analysis Signature (GSE26928) with increased expression in effector memory compared to central memory CD4 + cells. Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Sample numbers are shown below the heatmap, with an “A” prior to sample numbers indicating patients undergoing auto-HSCT. Samples without an “A” indicate patients treated with chemotherapy and not transplantation. Samples are ordered along the x-axis as in Fig. 1.

Fig. 5
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Fig. 5
A hierarchical clustering of transcripts from a Gene Set Enrichment Analysis Signature (GSE22045) with increased expression in regulatory T cells compared to conventional T cells. Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Samples are ordered along the x-axis as in Fig. 1.Stem Cell Treatments for Cancer Essay.

Fig. 6
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Fig. 6
A hierarchical clustering of transcripts from a Gene Set Enrichment Analysis Signature (GSE36476) with increased expression of transcripts that are more highly expressed in T cells from old versus young donors. Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Samples are ordered along the x-axis as in Fig. 1.Stem Cell Treatments for Cancer Essay.

Fig. 7
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Fig. 7
A hierarchical clustering of transcripts from a Gene Set Enrichment Analysis Signature (GSE9650) with a mixed pattern of expression of signatures associated with naïve versus exhausted CD8 + cells. Pre-treatment samples are on the left (grey bar above the heatmap) and post-treatment samples are on the right (blue bar). Sample numbers are shown below the heatmap, with an “A” prior to sample numbers indicating patients undergoing auto-HSCT. Samples without an “A” indicate patients treated with chemotherapy and not transplantation. Samples are ordered along the x-axis as in Fig. 1.

An analysis of specific genes altered by cancer therapy was also illuminating (selected transcripts are clustered in Fig. 1). For example, we observed a robust increase in transcripts associated generally with cellular senescence (e.g. CDKN2a, IL8, HMGA2, CCL4) (Narita et al., 2006, Acosta et al., 2008, Hammond and Sharpless, 2008, Cheng et al., 2015) or telomere shortening in T-cells (e.g. KLRK1, NUAK1, DSP, PIF1) (Humbert et al., 2010, Soriani et al., 2014, Textor et al., 2011, Lansdorp, 2007, Robin et al., 2014). Additionally, we noted changes that have been previously associated with T-cell aging and immunosenescence: decreased CD28 expression (Effros et al., 1994) and increased expression of several NK markers (e.g. CX3CR1, KLRK1, KLRA1) (Goronzy and Weyand, 2005, Sciume et al., 2011, Bauer et al., 1999, Bull et al., 2000). Consistent with the GSEA results and known patterns of human T-cell aging, there was a relative depletion of transcripts associated with central memory cells with an enrichment of transcripts associated with effector CD8 + T-cells (e.g. decreased CCR7 and IL7Rα, with increased GZMB, CD8a and NK markers (Fig. 1)). In accord with these processes, we observed that cancer therapy induced the expression of transcripts that are more highly expressed in T-cells from old versus young donors (Fig. 6). The effects on transcripts associated with T-cell exhaustion were less consistent: a few well-recognized markers of exhaustion significantly increased post-bone marrow insult (e.g. CD160 and LAG3, Fig. 1), whereas published signatures of T-cell exhaustion demonstrated a mixed pattern of expression in GSEA analysis (Fig. 7, see also Tables 8 and 9). These gene-specific data provide evidence beyond changes to p16INK4a (Table 2) that generic types of hematopoietic injury (e.g. forced bone marrow repopulation, cytotoxic chemotherapy) induces durable transcriptional changes characteristic of T-cell aging and immunosenescence, suggesting these insults accelerate T-cell molecular aging.Stem Cell Treatments for Cancer Essay.

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4. Discussion
In this work, we show that that DNA damaging chemotherapy and stem cell transplantation potently induce the transcriptional changes characteristic of aging in PBTL. This includes both changes associated with an altered composition of the T-cell organ with aging (e.g. decreased naïve and central memory cells versus increased effector memory cells and Tregs) as well as changes associated with telomere shortening and cellular senescence. While the notion that DNA damaging agents induce cellular senescence in vivo is non-controversial, a remarkable aspect of this work is the finding that autologous HSCT markedly induces the transcriptional changes of PBTL aging. For example, auto-HSCT increases the expression of p16INK4a, a highly dynamic marker of senescence, to a degree comparable ~ 30 years of chronological age. A similar increase in p16INK4a expression with auto-HSCT has been reported in myeloma patients (Rosko et al., 2015). As the autograft is not exposed to DNA damaging chemotherapy, this observation suggests that the forced proliferation that accompanies BM re-engraftment, even in the absence of exogenous clastogens, may be age-promoting in humans.Stem Cell Treatments for Cancer Essay.

In accord with prior work (Sanoff et al., 2014), we observed relatively increased expression of PBTL p16INK4a in pre-treatment samples from patients undergoing allogeneic, but not autologous stem cell transplant. This observation likely reflects differences in prior therapy between these two patient groups: with allogeneic HSCT patients having received high doses of alkylating agents and anthracyclines for acute leukemia, whereas autologous patients received largely non-cytotoxic anti-myeloma therapies such as bortezomib and lenalidomide. This observation suggests that cytotoxic chemotherapy may be more age-promoting than non-cytotoxic drugs used for myeloma, and is consonant with the practice of avoiding alkylating agents in patients with myeloma because such drugs impair subsequent stem cell collection (Clark and Brammer, 1998).Stem Cell Treatments for Cancer Essay.

It is perhaps surprising that autologous HSCT induces the strongest effect on PBTL molecular age, as measured by p16INK4a expression, of any noxious stimulus to date tested, including cytotoxic chemotherapy (Sanoff et al., 2014), chronic HIV infection (Nelson et al., 2012), tobacco use (Liu et al., 2009) or physical inactivity (Liu et al., 2009). We believe the most likely explanation for this finding is that the forced BM regeneration that accompanies re-engraftment induces intrinsic HSC aging. Serial transplant readily ‘exhausts’ HSC in murine models (Harrison, 1979), leading to a ‘myeloid skewing’ characterized by a marked decline in the per HSC capacity to produce naïve T-cells (Janzen et al., 2006), an observation that is in accord with our RNAseq analysis (Fig. 3). Furthermore, though pre-treatment samples from patients undergoing allogeneic HSCT had higher PBTL p16INK4a expression than those from patients undergoing autologous HSCT, it is possible that pre-transplant therapy had some age-promoting effect upon PBTLs in autologous HSCT recipients. Thus, in combination with forced BM regeneration, PBTLs of autologous HSCT recipients were “aged” twice due to therapy and then transplant, possibly helping to explain the larger effect on PBTL p16INK4a expression from autologous in comparison with allogeneic HSCT.Stem Cell Treatments for Cancer Essay.

Beyond an effect on HSC, however, it is possible that damage to other tissues contributes to this effect. For example, the thymus is damaged by pre-transplant conditioning with high-dose chemotherapy, and it is likely that graft-derived T-cells produced via a dysfunctional thymus exhibit accelerated aging (Min et al., 2005, Montecino-Rodriguez et al., 2013, Dorshkind et al., 2009, Linton and Dorshkind, 2004). Moreover, it is possible that not all host hematopoietic stem cells and self-renewing T-cells are destroyed by the conditioning regimen, and these surviving cells could exhibit accelerated aging as a result of exposure to conditioning. Since our analysis is performed on pooled PBTL, even a rare population of surviving cells that highly express p16INK4a could affect a post-transplant sample’s results. While such effects could affect PBTL p16INK4, it is unlikely that thymic damage or very rare surviving host T-cells would cause the wholesale transcriptional effects observed in the RNAseq analysis.Stem Cell Treatments for Cancer Essay.

Our finding that post-transplant senescent T-cells were biased toward the expression of transcripts associated with CD8 + effector cells and NK cells is consistent with prior studies of T-cell aging and immunosenescence.Stem Cell Treatments for Cancer Essay. (Perillo et al., 1993, Jaruga et al., 2000, Lemster et al., 2008). In aggregate, our work and other studies suggest that noxious stimuli such as DNA damage, telomere shortening and forced regeneration mimic the effects of chronologic age to augment the production of hypo-replicative T-cells with distinct immunophenotype (e.g. CD8 + CD28-) that express effector molecules such as Granzyme B and NK markers as well as markers of cellular senescence (e.g. p16INK4a and IL8). Such senescence-promoting stimuli have a more complex effect on markers of T-cell exhaustion, leading to increased expression of some exhaustion-associated markers and decreased expression of others. This finding is in accord with the notion that there are at least two different types of severely hyporeplicative states induced by excess T-cell proliferation—cellular senescence and exhaustion (Akbar and Henson, 2011)—with our work suggesting forced replication and DNA damaging agents induce the former, but not the latter, in humans.Stem Cell Treatments for Cancer Essay.

This work has several implications. First, it is possible that an assessment of T-cell molecular age could be used to predict suitability for transplantation. In fact, prior studies have shown that older autologous HSCT recipients have a higher likelihood than younger recipients of failing to achieve complete peripheral blood count recovery at 1 year, particularly true in patients who have been exposed to prior cytotoxic chemotherapy (Woolthuis et al., 2014, Bhatia et al., 2005). Such a use would be similar to the suggestion that a renal allograft’s molecular age, as measured by p16INK4a expression, is a stronger predictor of long-term graft function than donor age or telomere length (Koppelstaetter et al., 2008, Mcglynn et al., 2009, Gingell-Littlejohn et al., 2013). Larger studies with longer follow-up would be needed to confirm the hypothesis that donor molecular age of HSC influences long-term hematopoietic graft function.Stem Cell Treatments for Cancer Essay. Second, post-transplant T-cell senescence may have important implications with regard to T-cell function, with an increase in the frequency of senescent T-cells leading to greater long-term risk of infection or decreased response to vaccination (Targonski et al., 2007). Additionally, if increased molecular age of PBTL is the result of intrinsic HSC aging, this marker could also perhaps predict other late complications of HSCT such as bone marrow failure, MDS or secondary leukemia. Third, the finding that HSCT and DNA damaging agents promote the molecular aging of T-cells suggests such agents may compromise the post-transplant ability to respond to therapies intended to activate exhausted T-cells (e.g. anti-PD1 antibodies). Finally, the significant increase in T-cell senescence after HSCT further raises questions about the potential long term risks related to accelerated aging in recipients of two transplants (e.g. tandem autologous transplantation). For diseases in which credible non-transplant treatment approaches exist, pre-transplant “molecular age” and subsequent risk for further transplant-related accelerated aging could impact clinical decision-making.Stem Cell Treatments for Cancer Essay.

We acknowledge limitations to our work. First, we did not have data to demonstrate a correlation between the observed changes in biomarker expression with T cell function. However, inasmuch as p16INK4a expression is arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration (Baker et al., 2016), the signal of increased senescence early after transplantation is clear and concerning, even if a clearer explanation of this phenomena requires further study.Stem Cell Treatments for Cancer Essay. Second, other aspects of post-transplant immune reconstitution also influence the relative contribution of CD8 and CD4 T cells to the CD3 population in the early post-transplant period. Third, the relative contribution of clinical factors to PBTL p16INK4a expression, including graft versus host disease, infection, and use of immunosuppressive agents, could not be discerned in this analysis. Fourth, we did not have sequential longitudinal post-transplant samples available to study changes in p16INK4a expression over time. Fifth, donor samples were limited. We were unable in this study to determine the source of the T cells that were undergoing changes in biomarker expression following allogeneic transplantation; a clear idea of which cells were donor-derived and which were recipient-derived would help to discern the relative effects of chemotherapy vs transplant upon p16INK4a expression.Stem Cell Treatments for Cancer Essay.

In summary, we have shown that HSCT and cancer therapy strongly increase the expression in T cells of p16INK4a, a well-known biomarker of cellular senescence. Further, this likely occurs via an effect on hematopoietic stem cells. p16INK4a expression was markedly increased following transplantation, and in association with amount and certain types of chemotherapy. This observation may have implications for the management of patients with cancer as well as cancer survivors, in order to limit pro-aging effects of treatment and to protect against the development of frailty and other aging-related syndromes. Additional studies to investigate the relationships between T-cell aging and adverse outcomes following cancer therapy are warranted.Stem Cell Treatments for Cancer Essay.

A new problem has emerged with the ever-increasing number of breast cancer survivors. While early screening and advances in treatment have allowed these patients to overcome their cancer, these treatments often have adverse cardiovascular side effects that can produce abnormal cardiovascular function. Chemotherapeutic and radiation therapy have both been linked to cardiotoxicity; these therapeutics can cause a loss of cardiac muscle and deterioration of vascular structure that can eventually lead to heart failure (HF). This cardiomyocyte toxicity can leave the breast cancer survivor with a probable diagnosis of dilated or restrictive cardiomyopathy (DCM or RCM).Stem Cell Treatments for Cancer Essay. While current HF standard of care can alleviate symptoms, other than heart transplantation, there is no therapy that replaces cardiac myocytes that are killed during cancer therapies. There is a need to develop novel therapeutics that can either prevent or reverse the cardiac injury caused by cancer therapeutics. These new therapeutics should promote the regeneration of lost or deteriorating myocardium. Over the last several decades, the therapeutic potential of cell-based therapy has been investigated for HF patients. In this review, we discuss the progress of pre-clinical and clinical stem cell research for the diseased heart and discuss the possibility of utilizing these novel therapies to combat cardiotoxicity observed in breast cancer survivors.Stem Cell Treatments for Cancer Essay.

Keywords: chemotherapy–cardiotoxicity, stem cells, cardiac regeneration, differentiation, paracrine factors
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Advances in cancer treatments have led to a significant reduction in the incidence of mortality amongst breast cancer patients; a major accomplishment of today’s cancer therapies. The 5-year survival rate for females in the United States is 89%, and 78% at 15 years (1). Associated with increased breast cancer survival is an increase in cardiovascular co-morbidities (2). The scope of this issue has not been adequately studied and is not readily ascertained from clinical trial data on emerging chemotherapeutic agents. Clinical trials often consist of small cohorts of patients with under representation of specific patient populations and exclude those with co-morbidities. In addition, the incidence of adverse cardiac events has usually not been evaluated.Stem Cell Treatments for Cancer Essay. It is not surprising that novel cancer therapeutics can cause adverse cardiac events given the fact that cancer drugs influence cell survival (3–5). In concert with these novel reagents, some cancer treatment plans incorporate classical chemotherapeutics (anthracyclines) that are known to be more toxic to the cardiovascular system (6–8). Whether the pathways (survival and growth) by which these agents inhibit tumor progression overlap with those which preserve cardiovascular cell physiology, remains largely unknown. In our view, there is a need to investigate different therapeutics strategies to combat any adverse cardiovascular event observed in cancer patients.Stem Cell Treatments for Cancer Essay.

Cancer therapeutics cause cardiomyopathy in large part by causing the death of cardiac myocytes and supportive tissue (4, 5, 9–14). Therefore, cell therapies that repair existing myocardium or regenerate new myocardium to replace lost tissue could improve cardiac function in cancer survivors. Researchers and physician-scientist have been investigating cell-based therapy since the early 1980s (15).Stem Cell Treatments for Cancer Essay. In striving to understand the basic biology of adult stem cells, tremendous progress has been made in comprehending their therapeutic potential against disease states like acute myocardial infarction (AMI) and ischemic heart disease, culminating with numerous clinical trials since early 2002 (16). While still somewhat controversial, the scientific community is beginning to define the mechanism(s) responsible for the beneficial effects of those stem cell therapies tested to date. Regardless of the treatment strategy used to prevent or reverse adverse cardiovascular events in breast cancer patients, it will become increasingly important to screen patients, optimize treatment strategies, and monitor cardiac function prior to-, during-, and after cancer treatment.Stem Cell Treatments for Cancer Essay.

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Breast Cancer and the Etiology of Cardiotoxicity
In 2013, the projected number of new in situ and invasive breast cancer cases was just shy of 300,000 (1). Breast cancer death rates have been dropping since the early 1990s (1), due to better awareness by women to have annual mammograms, which has led to earlier detection and better success of treatment strategies. With over 2.9 million women living in the United States with a medical history indicating breast cancer (17), there has become a greater need for an understanding of the therapeutics utilized to combat breast cancer and their potential effects on other organ systems.Stem Cell Treatments for Cancer Essay.

Physicians have a variety of treatment options and strategies to slow, inhibit, and/or eliminate breast cancer. Newer generation chemotherapeutics have the capability of targeting specific pathways; usually interrupting cell survival (3, 8, 11, 18–20), growth (21), and proliferation (3, 8, 11, 18, 22, 23). Selective targeting therapeutics are a true testament to the amount a basic and clinical research that has gone into comprehending cancer biology over the last several decades. Ideal cancer therapeutics should affect cancer cells without effects on normal tissues.Stem Cell Treatments for Cancer Essay. Unfortunately even target specific agents have “off target” effects on normal cells in the heart and other tissues. Radiation therapy has also been improved as a therapeutic against breast cancer. With advances in technology, clinicians have the ability to more accurately direct the radiation treatment while minimizing the dose need; but still there are major side effects observed with both treatment options, and the incidence of cardiotoxicity is on the rise (24).Stem Cell Treatments for Cancer Essay.

While treatment may lead directly to cardiovascular dysfunction in some patients, in others it may hinder their ability to cope with preexisting or newly acquired cardiovascular diseases such as ischemic heart disease and hypertension.Stem Cell Treatments for Cancer Essay. It is important to point out that only a fraction of patients in chemotherapeutic clinical trials have reported adverse cardiac events (25, 26); 4–7% of patients in initial trials suffered from cardiotoxicity when treated with monoclonal antibody chemotherapeutics, which manifested itself as a decrease in left ventricular ejection fraction (LVEF) (27). This percentage was drastically increased (27%) when patients were treated concurrently with adjuvant chemotherapeutics, like anthracyclines (14).Stem Cell Treatments for Cancer Essay.

There are several hypotheses as to mechanism by which chemotherapeutic treatment initiates and/or exacerbates cardiotoxicity observed in breast cancer patients (4, 11, 12). The more classical drugs, like anthracyclines, most notably Doxorubicin, have been linked to greater increase in reactive oxygen species (ROS) causing more stress at the cellular level (10, 28, 29).Stem Cell Treatments for Cancer Essay. In cardiomyocytes, there is an abundance of mitochondria, which produce free radicals from anthracyclines, which are taken-up by the cell (30). This predisposes cardiac tissue to create high levels of ROS. This suggests high levels of newly formed ROS limits the amount of antioxidants that are found endogenously. With depletion of these much needed antioxidants, homeostasis is not maintained leading to an unfavorable cellular environment. A single basic research study, by De Angelis et al., looked directly at mechanisms by which chemotherapeutics are cardiotoxic and their effects on endogenous cardiac stem cells (CSC’s) (31), which are thought to be involved in endogenous cardiac repair. It was shown that classic chemotherapeutics (anthracyclines) increased ROS formation, caused DNA damage, induced p53 expression and cell cycle arrest in the G2/M phase, while decreasing CSC growth (31).Stem Cell Treatments for Cancer Essay.

Cardiotoxicity due to radiation therapy predominantly leads to pericardial and coronary vasculature damage. While early radiological practices lead to constrictive pericarditis; new technology and techniques to minimize the exposure of the heart to radiation and the incidence of pericarditis is still largely unknown due to limiting number of years post-technology development (32). Cell types, which are part of the coronary vascular framework have been shown to induce inflammation and lead to cardiovascular events, which can cause ischemic heart disease (33).Stem Cell Treatments for Cancer Essay. In a study which compared the effects of left- or right-sided radiation demonstrated an increase in coronary stenosis in patients who received left-side treatment; specifically the left anterior descending coronary artery (9). Again, with new techniques and better technology being utilized, this adverse event can be minimized.Stem Cell Treatments for Cancer Essay.

More reviews have come forth over the last several years discussing chemotherapeutic cardiotoxicity (3, 4, 8, 19, 20, 34–38) and there has been the formation of guidelines with clinical interdisciplinary cross talk between oncologists and cardiologists (11, 39–41) to more effectively treat the toxicity to organs such as the heart. Again, whether the primary treatment strategy is pharmacological or radiological, physicians have come to a consensus that adjuvant therapy increases the probability of initiating or exacerbating cardiotoxicity in breast cancer patients (4, 11, 12, 14). New basic, translational, and clinical studies will be essential to define the mechanisms of cardiotoxicity of chemotherapeutics and radiation therapy. It will also be important to carefully follow the increasing number of breast cancer survivors, to define their long-term cardiovascular risk.Stem Cell Treatments for Cancer Essay.

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Stem Cell Therapy
In this review, we suggest that stem cell therapy should be considered for cancer survivors who develop cardiomyopathy. Currently, one of the most impressive aspects of stem cell therapy for the heart is the wide variety of cell types that could be considered as potential candidates through pre-clinical (Table ​(Table1)1) and clinical research (Table ​(Table2).2). This reflects the true unmet need for a therapeutic avenue to be developed in order to treat and prevent the progression and manifestation of heart failure (HF) in patients who suffer cardiac injuries, like myocardial infarction or breast cancer therapy-induced cardiomyopathy. Here, we discuss endogenous cardiac regeneration and some of the more popular cell types that are being looked at as potential candidates for cell-based therapy.Stem Cell Treatments for Cancer Essay.

Table 1
Overview of animal studies with stem cell therapy.

Study Host Etiology of dysfunction Route of administration Outcomes
Orlic et al. (42) Mice Ligation of LAD IM ↑LV function
Mathieu et al. (43) Dog Ligation of LAD IM ↑LV function, ↓Scar
↓Brain natriuretic protein
Bel et al. (44) Sheep Ligation of CX IM No Δ LVEF or remodeling
Waksman et al. (45) Pig Permanent occlusion IM ↓Scar
Balsam et al. (46) Mice Ligation of LAD IM No trans-differentiation
Kajstura et al. (47) Mice Ligation of LAD IM ↑LV function, ↓Scar
Hatzistergos et al. (48) Pig I/R IM ↑LV function, ↓Scar
Homing of endogenous SCs
Cai et al. (49) Rat Ligation LAD IM ↑LV function
Quevedo et al. (50) Pig I/R IM ↑LV function, ↓Scar
Schuleri et al. (51) Pig I/R IM ↑LV function, ↓Scar
Linke et al. (52) Dog Occlusion of LAD IM ↑LV function
Beltrami et al. (53) Rat Ligation of LAD IM ↑LV function
Fischer et al. (54) Mice Ligation of LAD IM ↑LV function
Li et al. (55) Mice I/R IC ↑LV Function
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↑, Increase; ↓, decrease; No Δ indicates change; CX, circumflex coronary artery; LAD, left anterior descending coronary artery; I/R, ischemia-reperfusion; LV, left ventricle; IM, intramyocardial; IC, intracoronary.

Table 2
Overview of clinical trials with stem cell therapy.

Study No. patients Route of administration Primary end-point Outcomes
Perin et al. (56) Cell = 14 IM Echocardiography ↑LV function
Control = 7 ↓Remodeling
↓NYHA Class
Perin et al. (57) Cell = 11 IM Echocardiography No Δ LV function
Control = 9 ↑Exercise capacity
Galinanes et al. (58) Cell = 14 IM (during CABG) Dobutamine stress ↑LV function
No Control Echocardiography ↑Wall motion
Hendrikx et al. (59) Cell = 10 IM (during CABG) MRI No Δ LV function
Control = 10 ↓Remodeling
↓NYHA class
Fischer-Rasokat et al. (42) (TOPCARE-DCM) Cell = 33 IC MRI ↑LV function
No Control LV angiography ↑Wall Motion
Vrtovec et al. (60) Cell = 28 IC Echocardiography ↑LV function
Control = 27
Vrtovec et al. (56) Cell = 55 IC Echocardiography ↑LV function
Control = 55
Patel et al. (61) Cell = 10 IM (during CABG) Echocardiography ↑LV function
Control = 10
Hare et al. (62) (POSEIDON) Cell = 31 IM Computed tomography No Δ LV function
No Control ↓LVEDV
↑Physical performance
Karantalis et al. (63) Cell = 6 IM (during CABG) MRI ↑LV function, ↓Scar
No control
Bolli et al. (64) (SCIPIO) Cell = 16 IC Echocardiography ↑LV function, ↓Scar
Control = 7 MRI
Makkar et al. (65) (CADUCEUS) Cell = 17 IC MRI No Δ LV function, ↓Scar
Control = 8
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↑, increase; ↓, decrease; No Δ, no change; Cell, Cell-treated patients; CABG, coronary artery bypass graft surgery; LVEDV, left ventricular end-diastolic volume; NYHA, New York Heart Failure Association; LV, left ventricle; IM, intramyocardial; IC, intracoronary.

Cardiac regeneration
The heart has a limited capacity for repair after injury. This limited repair capacity is the bases for cardiac dysfunction after ischemic insult or damage from cancer chemotherapeutics. Why the heart has such a limited ability to repair itself and how cell therapy might enhance repair is an important topic in need of further study. Most questions about cardiac regeneration are still not resolved. Stem Cell Treatments for Cancer Essay.Interestingly, fish and other less developed species have an ability to regenerate lost portions of their hearts, primarily via proliferation of surviving myocytes that reenter the cell cycle (66, 67) post insult. This characteristic is also present in the fetal and early neonatal mammalian heart, but is generally absent in adult mammalian human heart tissue. Regardless of the robustness of endogenous cardiac repair it is clear that the adult human heart cannot repair itself after multiple forms of injury which can lead to HF.Stem Cell Treatments for Cancer Essay.

Adult cardiac myocytes are largely withdrawn from the cell cycle. Therefore the loss of myocytes with disease requires new myocyte formation to prevent cardiac functional decline. New myocytes could be derived from old myocytes that reenter the cell cycle or from a stem cell population with cardiogenic capacity. Some laboratories have demonstrated there is a small rate of turnover in myocytes in the adult heart (68–70) but not at a sufficient rate to repair the heart back to basal functional levels post injury. Other than cardiac transplantation, there is no therapy, which ultimately addresses the issues caused by myocardial injury and the progression of cardiac remodeling. With chemotherapeutic agents and radiation therapy affecting survival, growth, and proliferation pathways, while increasing oxidative stress and DNA damage, frank loss of heart muscle, and deterioration of myocardial support structure mimics other types of cardiac injury such as myocardial infarction. Whether this cardiotoxicity occurs acutely or chronically in breast cancer patients is unclear but the end result is most notably DCM or RCM (20, 31, 71–73).Stem Cell Treatments for Cancer Essay.

The fundamental principle that the human heart does not have an adequate endogenous repair mechanism has led to the discovery of isolating adult stem cells for use as a therapeutic for treating and preventing HF, which has exploded in the scientific research community and has given a new sense of hope to the idea of cell-mediated repair of the heart.Stem Cell Treatments for Cancer Essay.

Bone-marrow-derived stem cells
The bone-marrow is a diverse tissue that houses many cell types, including a variety of stem cells (56, 60, 74–76). Due to the ease of acquisition, with already approved clinical methods and their relatively high abundance, bone-marrow-derived stem cells have been and continue to be investigated as a possible source of cells that can be applied toward cardiac regeneration. This cell source is one of the most widely examined in pre-clinical experimentation and clinical trials to date. Here, we outline the major populations and their potential as cell therapy.Stem Cell Treatments for Cancer Essay.

Unfractionated bone-marrow mononuclear cells
Bone-marrow mononuclear cells are a heterogeneous mixture of multiple cell types [hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitors, and other more committed cell population] (57–59, 74). Through a density gradient centrifugation, bone-marrow mononuclear cells (BMMNCs) are isolated easily from whole bone-marrow fraction. With the easy of isolation and low maintenance in vitro, these cells have been utilized as a source of cell therapy in many animal models. In the acute MI setting, BMMNCs have shown much promise (42, 43). In contrast under chronic conditions of HF, the jury is still out; conflicting results in large animal models (43–45) and smaller scale preliminary clinical trials (77–79) still leave many questions as to the true mechanism(s) of action and the efficacy of this cell population. In a pig (45) model of HF, transplantation of BMMNCs provided no therapeutic benefit in terms of left ventricular (LV) function, but the study described an increase in angiogenesis and reduced infarct size. In another large animal study post infarct (43), BMMNC therapy showed an improvement in LV function, and reduced probrain natriuretic peptides (BNP) levels in the plasma, will also sparking angiogenesis.Stem Cell Treatments for Cancer Essay.

In the clinical arena, the results have been similar to the observations in the basic research community. The first clinical evaluation of BMMNCs as a therapeutic was performed by Perin et al. (77); 21 patients were enrolled (14 cell-treated and 7 control). Functional improvements were observed at 2–4 months; in patients receiving cell therapy there was a 9% increase in LVEF as compared to baseline and a reduction in the end-systolic volume (77). Stem Cell Treatments for Cancer Essay.Subsequent other trials confirmed these observations of improved cardiac function with intramyocardial injection of BMMNCs (78). In contrast, when cell were injected directly in the core of the damage region in 20 patients all beneficial effects were negated, there was no significant difference in LVEF or wall thickness by MRI (80). These vastly different outcomes have many factors, which may be playing a role in the results obtained, particularly the location of the injected cells. The microenvironment plays a pivotal role in the efficacy and any potential benefit cell therapy may have, as observed in these contrasting clinical trials (one with injection into the border zone of the infarct and the other into the core). In studies, which investigated the role of BMMNC therapy for non-ischemic cardiomyopathies there were promising results (81). BMMNCs therapy increase the regional LV function and improved microvascular function in Transplantation of Progenitor Cells and Recovery of LV Function In Patients With Non-ischemic Dilative Cardiomyopathy (TOPCARE-DCM), which enrolled 33 patients to receive intracoronary administration of BMMNCs (81).Stem Cell Treatments for Cancer Essay.

Studies of BMMNCs as a viable option for cell therapy have yielded inconsistent results both at the bench and in small scaled clinical trials, this is largely due to the heterogeneity of the cell population and the yield of actual progenitors in each isolation for therapeutic use. Larger scale trial’s must be run in order truly understand what effect(s) this cell type may be having as an option for cardiac regenerative therapy.Stem Cell Treatments for Cancer Essay.

Hematopoietic stem cells
Hematopoietic stem cells reside within the bone-marrow and commit to two different cell lineages, myeloid and lymphoid. The major cell surface marker which is used to distinguish this sub-population of cells from other progenitors which reside is in the bone-marrow is cluster differentiation 34 (CD34) (82–84); a transmembrane cell adhesion protein that has implicated in the literature to denote stem cells, which has a hematopoietic or vascular lineage. HSCs are mobilized from the bone-marrow into the peripheral blood during ischemic events to begin the process, which leads to revascularization (75). Researchers and clinicians felt that by isolating this population of cells and reintroducing them in more concentrated numbers would promote greater revascularization than observed by endogenous mechanisms post cardiac injury (46, 47, 75).Stem Cell Treatments for Cancer Essay.

Numerous clinical trials have been performed evaluating CD34+ cells in patients with both ischemic (61) and non-ischemic (56, 60) cardiomyopathy. Vrtovec et al. (56) looked to understand the beneficial effects of this cell population against non-ischemic cardiomyopathy by delivering the cells intracoronary to 55 of the 110 patients enrolled; this led to a ~5% increase in LVEF, improvement in the 6-min walk test and decreased probrain natriuretic peptide plasma levels. A 5-year follow-up study was able to demonstrate that the transplantation of these cells had an effect over a sustained period much longer than most trials (60).Stem Cell Treatments for Cancer Essay. The true mechanism by which this population of cells is having an effect is still not understood, but the major consensus amongst those in the field would be an increase in perfusion via revascularization. Preliminary clinical work with CD34+ hematopoietic cells is promising for both ischemic and non-ischemic cardiomyopathy, as with most of the cell types discussed here, a major limitation is the small sample sizes in these trials and lack of understanding as to the mechanism of action, which is due to an inability to apply standard methods utilized in basic research, toward human patients (i.e., immunohistochemistry, fluorescent microscopy, and molecular analysis).Stem Cell Treatments for Cancer Essay.

An important issue concerning this cell population is the fact that only autologous transplantations have been performed. For the average patient who has been enrolled in such Clinical trials to date, this resident population of cells can be easily harvested and utilized for cell-based therapy. In terms of the subset of patients discussed here, this may not be the case.Stem Cell Treatments for Cancer Essay. For individuals who have received or continue to undergo chemotherapy and radiation treatment, the CD34+ HSC population may be exhausted or non-existent all together (85, 86). This would subsequently eliminate this population of progenitors as a viable option for cell-based therapy to treat any cardiomyopathy induced by chemotherapeutic treatment of breast cancer. If this population of stem cells were to be beneficial against cardiotoxicity, it may be necessary for patients to undergo isolation prior to cancer treatment, so that cells could be isolated and expanded for future autologous cell-based therapy if needed. Other populations within the bone-marrow do exist and do not have to be autologous in nature for transplantation.Stem Cell Treatments for Cancer Essay.

Mesenchymal stem cells
Bone-marrow-derived MSCs are a sub-population of cells characterized by their adherence in culture (87). They also have begun to characterize a host of cell surface marker, which identifies this population within isolated bone-marrow. The majority of MSCs express CD29, CD73, CD90, and CD105 while being negative for hematopoietic lineage markers CD34 and CD45 (87, 88). Others have demonstrated sub-populations within the MSCs, which express these markers and a plethora of others (89, 90). The multipotentiality of these cells to differentiate into osteoblast, chondrocytes, adipocytes in vitro (91–94) is well documented and cardiomyocytes in vivo (95–97), which is still controversial (98). Paracrine signaling is one of the major mechanisms thought to elicit improvement by MSC therapy (48, 99) in the heart. This is due to release of numerous growth- (48), anti-apoptotic- (100, 101), and/or angiogenic- (49, 102) factors helping protect the myocardium and augment some of the adverse remodeling. Furthermore, MSCs demonstrate a capacity to engraft in a large animal model of MI (50, 51, 103) and have shown an ability to evade immune rejection (52, 104–106). In recent studies, results indicate MSC contributed directly to inhibition of inflammatory responses (107, 108), which may be the mechanism behind the observed reduction in scar size in both animal models and clinical trials (51, 62, 63). While there is still skepticism, this characteristic could allow MSCs to be used as an allogeneic source of cells, overcoming the need for isolation and expansion of autologous cell sources.Stem Cell Treatments for Cancer Essay.

With many clinical trials looking to understand the beneficial effect of numerous different cell types in patient suffering from cardiac related dysfunction, MSCs in recent years has become more popular for translational applications in patients (62, 63). Hare et al. (62) investigated MSC’s and their effect(s) on 15 of the 30 patient enrolled in the clinical trial Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON). This trial look to see if there was any dose dependent effect of MSC’s in patients who were suffering from ischemic cardiomyopathy (ICM). The data demonstrated, at all three doses, that MSC administration was favorable when measuring end-points of quality of life, functional capacity and ventricular remodeling (62). Krantalis et al. (63), in the Prospective Randomized Study of Mesenchymal Stem Cells Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial, investigated the injection of MSC’s in six patients receiving coronary artery bypass graft surgery (CABG). Those regions of the myocardium, which received cell therapy demonstrated a decrease in scar mass compared with baseline at 18 months follow-up (63). An overwhelming number of clinical trials that are “recruiting” encompass MSC’s therapy exclusively or as part of their treatment strategy (109). At this point, MSC’s are becoming more promising for clinical applications and widely investigated for the utility of cardiac regeneration in the clinical setting.Stem Cell Treatments for Cancer Essay.

Cardiac stem cells
Cardiac-derived stem cells have also been in the spot light of animal investigations and recently, clinical trials (53, 54, 65, 110–113). The discovery that the heart is in fact an organ, which has the ability to have cellular turnover and renewal (both of myocytes and non-myocytes) refutes the long withstanding dogma that the heart is a post-mitotic organ. This renewal is thought to be derived from a population of stem cells, which reside as niches within the myocardium (110). New methodology has been developed over the last decade to isolate (53) and characterize these cells in vitro (53, 111) and investigate their therapeutic potential. The isolation of CSCs has given hope that these cells will be predisposed to an increased probability of neomyogenesis as compared to other cell types discussed previously.

C-kit (+)/hematopoietic lineage (−) CSCs
This cell population was first described in 2003 by Beltrami et al., cells were isolated from a rodent heart (53). The manuscript describes a cell population isolated from cardiac tissue that expressed a tyrosine kinase receptor c-kit, now a known marker of stemness (53). This population not only fit the classical definition of a “stem cell” (self-renewing, clonogenic, and multipotent) but also differentiated into cardiomyocytes, smooth muscle cells, and endothelial cells in vitro and in vivo (53, 110, 111). Human cardiac c-kit+ positive cells were isolated some 4 years later (111). Since then, injection of isolated c-kit+ CSCs and studying the beneficial effects has been overwhelming; multiple laboratories and basic research studies have demonstrated that post injection an alleviation of LV dysfunction and adverse remodeling, while showing the elicit response of regeneration due to injection (54, 55, 114). With such positive outcomes in rodent models (54, 55, 115), this cell type was soon moved to a pre-clinical large animal model. Bolli et al. (64) investigate the role on intracoronary infusion of CSCs 3 months post-MI and found a significant difference in LVEF as compared to vehicle treated animals, while demonstrating increased wall thickness and beneficial changes in the maximal developed pressure, as well as, a lower diastolic pressure.Stem Cell Treatments for Cancer Essay. With that, this work in the large animal model laid the ground work for a human clinical trial investigating the efficacy and safety of CSC’s in patients. The Stem Cell Infusion in Patients with CardiOmyopathy (SCIPIO) clinical trial update discussed the infusion into the coronary circulation, 1 million c-kit+/lineage – CSC’s into 16 patients with LV dysfunction (113). The authors concluded that these cells produced better LV systolic function through reduction of scare size in patients with MI, and further clinical trials should be performed (113). With promising results in the phase I trial, CSCs are bidding to become the superior choice in choosing a cell type for cardiac cell therapy. While clinical trials are ongoing, there has only been one small animal study investigating the therapeutic potential of CSC therapy post chemotherapeutic cardiotoxicity, this study as discussed above (cardiotoxicity section) looked to solidify the mechanism by which the cardiotoxicity occurs and utilized c-kit+ CSCs as a therapeutic intervention to combat the adverse effects observed (31). De Angelis et al. (31) concluded that cell-based therapy promoted regenerative capacity of the myocardium, improved cardiac pump function, and decreased mortality.Stem Cell Treatments for Cancer Essay.

Collectively, with all the successes of pre-clinical and clinical trials to date, there is much more work that is needed to fully understand the therapeutic potential of cell-based therapy for all types of cardiac disease states regardless of the etiology.Stem Cell Treatments for Cancer Essay.

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Cell Therapy Potential for Chemotherapeutic/Radiation-Induced Cardiotoxicity in Breast Cancer Patients
With the plethora of basic science and clinical research performed on isolating and characterizing a number of adult stem cells to be utilized for cardiac cell therapy in the past two decades, we as a field still do not know which cell type, and/or combination of cells will be most beneficial. Stem Cell Treatments for Cancer Essay.The work has yielded some rewards despite most questions still not having answers; we now understand that multiple tissues have population of stem cells that have the capacity to be beneficial toward heart function post injury and inhibit adverse remodeling, while improving quality of life in patients suffering from many different cardiac disease states (15, 16, 42, 50, 51, 56, 62, 64, 69, 83, 100, 102, 113). Despite not fully understanding the mechanism of action, the field has a general consensus on ways in which stem cell therapy is working to improve cardiac function (Figure ​(Figure1);1); animal studies have shown beneficial effects of stem cell therapy through paracrine factor secretion (48, 99, 100), trans-differentiation into multiple cell types, which help to improve cardiac function (92, 116) and through homing of endogenous stem cells to the site of injury (48, 76). The cell types discussed above do not all work with the same mechanism of action; it has been demonstrated that MSCs most likely work through paracrine factor production and secretion (48, 51, 74, 117–119), while BMMNCs and CSCs have the ability to form new blood vessels for better perfusion (46, 47, 53–55, 59, 75–77, 79, 85, 86, 89, 96, 110, 120, 121) and create new myocyte from transplanted cells (53, 55, 64, 111–115, 122, 123). Below, we discuss the major mechanisms and how they may be beneficial toward patients suffering from cancer treatment-related cardiotoxicity.

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Figure 1
Proposed mechanisms of stem cell-mediated repair. Transplantation of stem cells into the heart initiates repair of damaged tissue. The hypothesized repair mechanisms are both direct and indirect, trans-differentiation of stem cells into new cardiomyocytes and vascular cells, inhibition of apoptosis, mobilization of endogenous cell populations, alterations in ECM remodeling, and neovascularization. Collectively, these processes reduce adverse cardiac remodeling, increase the possibility of perfusion, repair/regenerate damaged tissues, and ultimately improve left ventricular cardiac pump function & patients clinical end-points. Illustration credit: Thomas E. Sharp III.Stem Cell Treatments for Cancer Essay.

Trans-differentiation of transplanted cells
The logical explanation for using stem cell therapy to repair the heart is the idea in which transplanted cells will form new myocardium replacing lost or damage tissue. As obvious as this may seem, data acquired thus far in the field of cardiac regeneration would suggest that little trans-differentiation is actually occurring, and that this is probably the least likely mechanism of action for the observed improvements post therapy. Much of the debate still goes on as to the amount or proportion of beneficial effects that should be attributed toward trans-differentiation. Still highly controversial is the notion that cell populations derived from the bone-marrow (HSC’s, MSC’s, and CD34+ SC’s) form new cardiac myocytes; numerous laboratories have evidence supporting such notions (124, 125), while others contest these conclusions (46, 126). Alternatively, some suggest that the mechanism of action is fusion of the injected cells with endogenous surviving myocytes (127, 128). Discussed in more detail below, most would agree that the major mechanism of action may be paracrine factor production and secretion (100, 101). While in the acute MI disease model, there is strong evidence for trans-differentiation (53, 110, 129–131); in the post-MI HF large animal model the data would suggest that the amount of trans-differentiation observed is insufficient to explain the significant increase in cardiac function post injury and after therapeutic intervention (64). In recent years, the debate has turned more toward understanding the proportion of new myocyte formation in the different cell types (discussed above) and how the quantification of this trans-differentiation is proportionate or disproportionate to the improved cardiac function. In patients suffering cancer therapy cardiotoxicity, trans-differentiation of transplanted stem cells may allow for the replacement of cells that may otherwise have died from necrosis (132) or other proposed mechanisms (3, 6, 14, 18–20, 31, 36, 38, 133) due to chemotherapeutic treatment and in turn limit the amount of fibrosis which develops. In limiting the fibrosis, in patients suffering from chemotherapeutic/radiation cardiotoxicity, we would anticipate less adverse remodeling and subsequently better outcomes over time. As discussed above, this mechanism is likely unable to account for any or all the benefit which may occur in these patients post-stem cell treatment.Stem Cell Treatments for Cancer Essay.

The creation of new blood vessels de novo may be of great benefit to patients who suffer from chronic or persistent coronary occlusion, which develops into ICM. This may occur in cancer patients due to the anti-angiogenic nature of classical chemotherapeutics (3, 5, 40) and frank loss of vascular structure from radiation therapy. On the contrary, those who suffer from non-ischemic cardiomyopathy, it is difficult to see the beneficial aspects of utilizing cells which have demonstrated in experimental models to create new vasculature. What may be the most important mechanism or alternative action, which has allowed for the most benefit, is paracrine factor production/secretion and signaling.Stem Cell Treatments for Cancer Essay.

Paracrine signaling
In reality, the inability (up to now) to solidify the mechanism of action by which stem cells act on the heart has led to great emphasis on the paracrine hypothesis (100). This concept hypothesizes that transplanted cells modulate the myocardial milieu in the injury site by secreting factor that signal to the surrounding cells and tissue(s). Paracrine signal may in fact promote a multitude of reparative and regenerative processes, like: promoting cell survival, the inhibition of cell apoptosis, promoting a new blood vessel formation, favorable changes to the extracellular matrix (ECM), modulation of the inflammatory response which occurs upon injury, and activation/homing of endogenous stem cell populations to the site of injury. This signaling can also play a key role in the ability for transplanted stem cells to thrive in a harsh environment by autocrine signaling and positive feedback loops. In concert, these actions promote better LV function and slower progression of remodeling and development of HF.Stem Cell Treatments for Cancer Essay.

Cell survival and inhibition of apoptosis
Numerous basic research studies have suggested the production and secretion of paracrine factors [like, insulin like growth factor-1 (IGF1) and secreted frizzled-related protein-2 (SFRP2)] inhibit cardiomyocyte apoptosis (101, 134). Another parameter, which may assist in the pro-survival hypothesis is the modulatory affect of the stem cells toward the immune response (101, 108, 135). In augmenting the immune response one could hypostulate less activation of the positive feedback loop within the innate and adaptive immune responses to cardiac injury. This in turn, would limit cell death and deposition of ECM proteins, which could potential preserve the myocardium and LV function.

In a recent study of a rodent model of MI, Duran et al. (136) was able to demonstrate the production of specific paracrine factors by stem cells, which promote angiogenesis and incorporation of stem cells into newly formed vasculature in vivo. Multiple cell populations have been described as producing angiogenic factor such as: fibroblast growth factor-2 and -7 (FGF) (137), platelet-derived growth factor (PDGF) (138), and vascular endothelial growth factor (VEGF) (100, 137). With chemotherapeutics being highly toxic and anti-angiogenic (3, 5, 40), utilizing stem cell therapy to maintain/repair vasculature and promote the neovascularization of areas, which may be lacking blood supply is an important idea. While some may caution the notion of promoting neovascularization and angiogenesis in patient suffering from cancer in fear of potentially promoting vascularization of present tumors and causing metastasis, one should withhold their reservations, as techniques, which are used to deliver the stem cells are usually performed locally within the organ [intracoronary delivery (55, 64, 65, 102, 121, 139, 140) and intramyocardial injection (77, 119, 141–143)]. Aside from this minor concern, this therapeutic benefit from stem cell administration is one of the more promising for patients who have been administered chemotherapeutics or undergone radiation treatment, which are hailed for the ability to inhibit vasculature formation.Stem Cell Treatments for Cancer Essay.

ECM remodeling
Under the paracrine hypothesis, stem cells have been ascribed the ability to augment deleterious alterations in the ECM (138, 144–146). Post stem cell therapy has shown in rodent models of MI to reduction in scar size, reduced fibrosis, and subsequently inhibition of LV remodeling (74, 118, 137, 140, 146–148). While there is no significant scar formation in patients who suffer direct cardiotoxicity from chemotherapy, the reduction in fibrosis may play an important role in these patients. In having the capacity to change the cell niche with which myocardial cells reside is an important factor, as most chemotherapeutic cardiotoxicity is not due to ischemia, rather a change in the abundance of fibrosis in the cellular milieu (3, 5, 13, 20, 40) and cell death.Stem Cell Treatments for Cancer Essay.

Homing of endogenous progenitor populations
With a wide variety of paracrine factors being produced by stem cells, specific factors have been implicated in mobilizing and homing endogenous stem cells pools to the site of injury or sites of transplantation of exogenous cells (48, 140). Such factor include: stem cell-derived factor (SDF) (138), hepatocyte growth factor (HGF), and IGF (100, 101). These factor collectively permit endogenous stem cell homing, proliferation, and differentiation into myocardial cell types (myocytes and vascular cells), concurrently with some of the other beneficial effects observed with such factors as IGF [which has demonstrated to be pro-survival (101)]. In patients who have undergone chemotherapy, this mechanism of mobilizing native stem cells is probably not likely, as with most of the basic research studies performed thus far have concluded that chemotherapeutics are deleterious to endogenous stem cell population (23, 31, 132, 149).Stem Cell Treatments for Cancer Essay.

Autocrine signaling
While the paracrine signaling hypothesis discusses the therapeutic nature of growth factor signaling on endogenous tissue(s), the hypothesis has also given rise to scientific investigation of this signaling on the cells, which produces them. Many laboratories have demonstrated that autocrine signaling of growth factors and factors of stemness are necessary for self-renewal, maintenance, survival, and growth. FGF (150–152) has been shown to drive self-renewal, inhibit cellular senescences, and inhibit apoptosis. While others have demonstrated that SDF plays a critical role in survival and maintenance of the stem cell(s) (153). This paracrine/autocrine signaling may help enhance the other effects that transplanted cells may have on endogenous tissue by allowing the transplanted cells to be retained and produce more of these factors, while also enhancing the possibility of trans-differentiation, due to longer retention.Stem Cell Treatments for Cancer Essay.

While these major mechanisms of action are being vetted in animal models, one thing has become certain; the therapeutic benefit of stem cells is not exclusively made up of a single mechanism but more likely multi-factorial and in different proportions depending on the stem cell population chosen for therapeutic intervention. While most studies have not looked at stem cells therapy for chemotherapeutic/radiation cardiotoxicity, some basic research publications have indicated improvement with stem cell administration (31).Stem Cell Treatments for Cancer Essay.

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Challenges Facing Cell-Based Therapy
With any novel therapeutic in the R & D phase there are many unknowns and obstacles, which must be investigated. Clinical trials of stem cells therapy for patients suffering from cardiac pathologies similar to those observed in patients with chemotherapeutic/radiation cardiotoxicity have shown promise (56, 62, 65, 77, 78, 113, 121, 154, 155), but there is more work needed to be done in order to truly understand the mechanisms behind the improved cardiac function. Once recognizing and establishing more concrete comprehension of the therapeutic benefit of such an intervention, the medical community will be able to make a more informed decision as to whether or not stem cells are a viable option for treatment of chemotherapeutic cardiotoxicity. There are many questions, which are still unresolved, for example: (1) understanding what stem cell populations are optimal for regeneration, (2) is there a dose dependent effect, and (3) what time points should cell therapy be administered and how frequent. These issues can only be answered with more careful planned pre-clinical and clinical trials, not only for more broad cardiac disease states (like acute MI and congestive HF), but also in concentrating on understanding the negative effects of chemotherapeutic/radiation cardiotoxicity and the potential of cell-based therapy in this context. With this, we believe that stem cell-based therapy is one of the frontiers still left in medicine today. There is an enormous amount of potential for regenerative medicine in context of the heart and will probably be a viable option for the treatment of chemotherapeutic/radiation-induced cardiotoxicity.Stem Cell Treatments for Cancer Essay.

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Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Bone marrow is the soft, sponge-like material found inside bones. It contains immature cells known as hematopoietic or blood-forming stem cells. (Hematopoietic stem cells are different from embryonic stem cells. Embryonic stem cells can develop into every type of cell in the body.) Hematopoietic stem cells divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: white blood cells, which fight infection; red blood cells, which carry oxygen; and platelets, which help the blood to clot. Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants.Stem Cell Treatments for Cancer Essay.

What are bone marrow transplantation and peripheral blood stem cell transplantation?

Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:Stem Cell Treatments for Cancer Essay.

In autologous transplants, patients receive their own stem cells.
In syngeneic transplants, patients receive stem cells from their identical twin.Stem Cell Treatments for Cancer Essay.
In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Why are BMT and PBSCT used in cancer treatment?

One reason BMT and PBSCT are used in cancer treatment is to make it possible for patients to receive very high doses of chemotherapy and/or radiation therapy. To understand more about why BMT and PBSCT are used, it is helpful to understand how chemotherapy and radiation therapy work.

Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to treat cancer because cancer cells divide more often than most healthy cells. However, because bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT and PBSCT replace stem cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s ability to produce the blood cells the patient needs.Stem Cell Treatments for Cancer Essay.

In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial to the effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cells that remain in the patient’s body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them.

What types of cancer are treated with BMT and PBSCT?

BMT and PBSCT are most commonly used in the treatment of leukemia and lymphoma. They are most effective when the leukemia or lymphoma is in remission (the signs and symptoms of cancer have disappeared). BMT and PBSCT are also used to treat other cancers such as neuroblastoma (cancer that arises in immature nerve cells and affects mostly infants and children) and multiple myeloma. Researchers are evaluating BMT and PBSCT in clinical trials (research studies) for the treatment of various types of cancer.Stem Cell Treatments for Cancer Essay.

How are the donor’s stem cells matched to the patient’s stem cells in allogeneic or syngeneic transplantation?

To minimize potential side effects, doctors most often use transplanted stem cells that match the patient’s own stem cells as closely as possible. People have different sets of proteins, called human leukocyte-associated (HLA) antigens, on the surface of their cells. The set of proteins, called the HLA type, is identified by a special blood test.Stem Cell Treatments for Cancer Essay.

In most cases, the success of allogeneic transplantation depends in part on how well the HLA antigens of the donor’s stem cells match those of the recipient’s stem cells. The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells. In general, patients are less likely to develop a complication known as graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched.Stem Cell Treatments for Cancer Essay.

Close relatives, especially brothers and sisters, are more likely than unrelated people to be HLA-matched. However, only 25 to 35 percent of patients have an HLA-matched sibling. The chances of obtaining HLA-matched stem cells from an unrelated donor are slightly better, approximately 50 percent. Among unrelated donors, HLA-matching is greatly improved when the donor and recipient have the same ethnic and racial background. Although the number of donors is increasing overall, individuals from certain ethnic and racial groups still have a lower chance of finding a matching donor. Large volunteer donor registries can assist in finding an appropriate unrelated donor.Stem Cell Treatments for Cancer Essay.

Because identical twins have the same genes, they have the same set of HLA antigens. As a result, the patient’s body will accept a transplant from an identical twin. However, identical twins represent a small number of all births, so syngeneic transplantation is rare.Stem Cell Treatments for Cancer Essay.

How is bone marrow obtained for transplantation?

The stem cells used in BMT come from the liquid center of the bone, called the marrow. In general, the procedure for obtaining bone marrow, which is called “harvesting,” is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted through the skin over the pelvic (hip) bone or, in rare cases, the sternum (breastbone), and into the bone marrow to draw the marrow out of the bone. Harvesting the marrow takes about an hour.Stem Cell Treatments for Cancer Essay.

The harvested bone marrow is then processed to remove blood and bone fragments. Harvested bone marrow can be combined with a preservative and frozen to keep the stem cells alive until they are needed. This technique is known as cryopreservation. Stem cells can be cryopreserved for many years.Stem Cell Treatments for Cancer Essay.

How are PBSCs obtained for transplantation?

The stem cells used in PBSCT come from the bloodstream. A process called apheresis or leukapheresis is used to obtain PBSCs for transplantation. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area). The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes 4 to 6 hours. The stem cells are then frozen until they are given to the recipient.Stem Cell Treatments for Cancer Essay.

How are umbilical cord stem cells obtained for transplantation?

Stem cells also may be retrieved from umbilical cord blood. For this to occur, the mother must contact a cord blood bank before the baby’s birth. The cord blood bank may request that she complete a questionnaire and give a small blood sample.

Cord blood banks may be public or commercial. Public cord blood banks accept donations of cord blood and may provide the donated stem cells to another matched individual in their network. In contrast, commercial cord blood banks will store the cord blood for the family, in case it is needed later for the child or another family member.Stem Cell Treatments for Cancer Essay.

After the baby is born and the umbilical cord has been cut, blood is retrieved from the umbilical cord and placenta. This process poses minimal health risk to the mother or the child. If the mother agrees, the umbilical cord blood is processed and frozen for storage by the cord blood bank. Only a small amount of blood can be retrieved from the umbilical cord and placenta, so the collected stem cells are typically used for children or small adults.Stem Cell Treatments for Cancer Essay.

Are any risks associated with donating bone marrow?

Because only a small amount of bone marrow is removed, donating usually does not pose any significant problems for the donor. The most serious risk associated with donating bone marrow involves the use of anesthesia during the procedure.Stem Cell Treatments for Cancer Essay.

The area where the bone marrow was taken out may feel stiff or sore for a few days, and the donor may feel tired. Within a few weeks, the donor’s body replaces the donated marrow; however, the time required for a donor to recover varies. Some people are back to their usual routine within 2 or 3 days, while others may take up to 3 to 4 weeks to fully recover their strength.Stem Cell Treatments for Cancer Essay.

Are any risks associated with donating PBSCs?

Apheresis usually causes minimal discomfort. During apheresis, the person may feel lightheadedness, chills, numbness around the lips, and cramping in the hands. Unlike bone marrow donation, PBSC donation does not require anesthesia. The medication that is given to stimulate the mobilization (release) of stem cells from the marrow into the bloodstream may cause bone and muscle aches, headaches, fatigue, nausea, vomiting, and/or difficulty sleeping. These side effects generally stop within 2 to 3 days of the last dose of the medication.Stem Cell Treatments for Cancer Essay.

How does the patient receive the stem cells during the transplant?

After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells through an intravenous (IV) line just like a blood transfusion. This part of the transplant takes 1 to 5 hours.

Are any special measures taken when the cancer patient is also the donor (autologous transplant)?

The stem cells used for autologous transplantation must be relatively free of cancer cells. The harvested cells can sometimes be treated before transplantation in a process known as “purging” to get rid of cancer cells. This process can remove some cancer cells from the harvested cells and minimize the chance that cancer will come back. Because purging may damage some healthy stem cells, more cells are obtained from the patient before the transplant so that enough healthy stem cells will remain after purging.Stem Cell Treatments for Cancer Essay.

What happens after the stem cells have been transplanted to the patient?

After entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as “engraftment.” Engraftment usually occurs within about 2 to 4 weeks after transplantation. Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer, however—up to several months for autologous transplant recipients and 1 to 2 years for patients receiving allogeneic or syngeneic transplants. Doctors evaluate the results of various blood tests to confirm that new blood cells are being produced and that the cancer has not returned. Bone marrow aspiration (the removal of a small sample of bone marrow through a needle for examination under a microscope) can also help doctors determine how well the new marrow is working.Stem Cell Treatments for Cancer Essay.

What are the possible side effects of BMT and PBSCT?

The major risk of both treatments is an increased susceptibility to infection and bleeding as a result of the high-dose cancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give the patient transfusions of platelets to prevent bleeding and red blood cells to treat anemia. Patients who undergo BMT and PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions.Stem Cell Treatments for Cancer Essay.

Potential long-term risks include complications of the pretransplant chemotherapy and radiation therapy, such as infertility (the inability to produce children); cataracts (clouding of the lens of the eye, which causes loss of vision); secondary (new) cancers; and damage to the liver, kidneys, lungs, and/or heart.Stem Cell Treatments for Cancer Essay.

With allogeneic transplants, GVHD sometimes develops when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver, and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronic GVHD). To prevent this complication, the patient may receive medications that suppress the immune system. Additionally, the donated stem cells can be treated to remove the white blood cells that cause GVHD in a process called “T-cell depletion.” If GVHD develops, it can be very serious and is treated with steroids or other immunosuppressive agents. GVHD can be difficult to treat, but some studies suggest that patients with leukemia who develop GVHD are less likely to have the cancer come back. Clinical trials are being conducted to find ways to prevent and treat GVHD.Stem Cell Treatments for Cancer Essay.

The likelihood and severity of complications are specific to the patient’s treatment and should be discussed with the patient’s doctor.Stem Cell Treatments for Cancer Essay.

What is a “mini-transplant”?

A “mini-transplant” (also called a non-myeloablative or reduced-intensity transplant) is a type of allogeneic transplant. This approach is being studied in clinical trials for the treatment of several types of cancer, including leukemia, lymphoma, multiple myeloma, and other cancers of the blood.Stem Cell Treatments for Cancer Essay.

A mini-transplant uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for an allogeneic transplant. The use of lower doses of anticancer drugs and radiation eliminates some, but not all, of the patient’s bone marrow. It also reduces the number of cancer cells and suppresses the patient’s immune system to prevent rejection of the transplant.Stem Cell Treatments for Cancer Essay.

Unlike traditional BMT or PBSCT, cells from both the donor and the patient may exist in the patient’s body for some time after a mini-transplant. Once the cells from the donor begin to engraft, they may cause the GVT effect and work to destroy the cancer cells that were not eliminated by the anticancer drugs and/or radiation. To boost the GVT effect, the patient may be given an injection of the donor’s white blood cells. This procedure is called a “donor lymphocyte infusion.”Stem Cell Treatments for Cancer Essay.

What is a “tandem transplant”?

A “tandem transplant” is a type of autologous transplant. This method is being studied in clinical trials for the treatment of several types of cancer, including multiple myeloma and germ cell cancer. During a tandem transplant, a patient receives two sequential courses of high-dose chemotherapy with stem cell transplant. Typically, the two courses are given several weeks to several months apart. Researchers hope that this method can prevent the cancer from recurring (coming back) at a later time.Stem Cell Treatments for Cancer Essay.

How do patients cover the cost of BMT or PBSCT?

Advances in treatment methods, including the use of PBSCT, have reduced the amount of time many patients must spend in the hospital by speeding recovery. This shorter recovery time has brought about a reduction in cost. However, because BMT and PBSCT are complicated technical procedures, they are very expensive. Many health insurance companies cover some of the costs of transplantation for certain types of cancer. Insurers may also cover a portion of the costs if special care is required when the patient returns home.

There are options for relieving the financial burden associated with BMT and PBSCT. A hospital social worker is a valuable resource in planning for these financial needs. Federal government programs and local service organizations may also be able to help.Stem Cell Treatments for Cancer Essay.

NCI’s Cancer Information Service (CIS) can provide patients and their families with additional information about sources of financial assistance at 1–800–422–6237 (1–800–4–CANCER). NCI is part of the National Institutes of Health.

What are the costs of donating bone marrow, PBSCs, or umbilical cord blood?

All medical costs for the donation procedure are covered by Be The Match®, or by the patient’s medical insurance, as are travel expenses and other non-medical costs. The only costs to the donor might be time taken off from work.Stem Cell Treatments for Cancer Essay.

A woman can donate her baby’s umbilical cord blood to public cord blood banks at no charge. However, commercial blood banks do charge varying fees to store umbilical cord blood for the private use of the patient or his or her family.Stem Cell Treatments for Cancer Essay.

Where can people get more information about potential donors and transplant centers?

The National Marrow Donor Program® (NMDP), a nonprofit organization, manages the world’s largest registry of more than 11 million potential donors and cord blood units. The NMDP operates Be The Match®, which helps connect patients with matching donors.Stem Cell Treatments for Cancer Essay.

A list of U.S. transplant centers that perform allogeneic transplants can be found at Disclaimer The list includes descriptions of the centers, their transplant experience, and survival statistics, as well as financial and contact information.

Stem Cell Center” offers a complete scope of stem cell solutions in India for the treatment of various types of diseases. Our main focus is helping people get back to good health through stem cell treatment. Our organization associated with so many hospitals, medical tourism company and also has our own stem cell research labs in India to provide best quality of stem cells in this advanced stem cell treatment field to provide best quality of treatment for all needed patients al over the world.Stem Cell Treatments for Cancer Essay.

We also provide complete stem cell lab set up in all over the world and started some other stem cells labs in other countries via our best and experienced team. We have more than 10 years stem cell research experience and treated more than thousand patients for various diseases and even provide stem cell services to various hospitals in all over the world.Stem Cell Treatments for Cancer Essay.

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We are giving advanced Stem Cell Therapy in India where all other medical treatment fail then this stem cell treatment apply to cure such non-treatable maladies or diseases.Stem Cell Treatments for Cancer Essay.

As the main healthcare consultant, stem cell center in India takes care of each and every section of the Medical Tourism Trip to entire India. We guarantee, our patients get the best healthcare service by getting in place, the renowned specialty hospitals, latest stem cell treatments, economical housing and alternatives for the patients.Stem Cell Treatments for Cancer Essay.

Our organization is giving best stem cell therapy in India and furthermore has perfection in stem cell treatment in Uttar Pradesh, Delhi NCR and all other all major cities of India for the required patients in all those application which can treat by stem cell therapy. We have stem cells in various forms to improve the better recuperation of patient and refer the best stem cell solutions after the evaluation of patient case study by our experts. Our experts in stem cell cooperate with patients however the total understanding to offer you more peace of mind to develop clear evidence based path. We have highly experts in our team and our experts are strong in research and clinical research from the two perspectives.Stem Cell Treatments for Cancer Essay.

Our mission is to offer best stem cell therapy at sensible price not only in India but also throughout the entire world so that every required patients can get best stem cell therapy to enhance his life.Stem Cell Treatments for Cancer Essay.